NL1026329C2 - 2-Amino-pyridine derivatives useful for the treatment of diseases. - Google Patents

Description

Ί 5 2-Amino-pyridine derivatives useful for the treatment of diseases

This invention relates to p2 agonists of general formula (1):

10 H H

I I. Λ I 4-Wv / O ’(1) A ^ ri R2 AA γ ·

H2fA N · O

Wherein R1, R2, n and Q1 have the meanings indicated below, and methods for the preparation of intermediates used in the preparation of compositions containing and the use of such derivatives.

Adrenoceptors are members of the large G-protein coupled receptor superfamily. The adrenoceptor subfamily. is itself divided into the α and β subfamilies where the β subfamily consists of at least 3 receptor subtypes: βΐ, 25 β2 and β3. These receptors exhibit different expression patterns in tissues from various mammalian systems and organs. β2 Adrenergic (β2) receptors are primarily expressed in smooth muscle cells (eg, vascular, bronchial, uterine or intestinal smooth despatches), while β3 adrenergic receptors are primarily expressed in adipose tissue (therefore, p3 agonists might be useful in the treatment of obesity and diabetes) and βΐ adrenergic receptors are primarily expressed in heart tissues (therefore βΐ-agonists are mainly used as cardiac stimulants).

Pathophysiology and treatments of respiratory diseases have been extensively discussed in the literature (for reference see Barnes, PJ Chest, 1997, 111: 2, pp. 17S-26S and I Bryan, SA et al., Expert Opinion on investigational drugs, I 5 2000, 9: 1, pp. 25-42) and therefore will only be a concise one

I summary are included here for some background information

To provide information.

Glucocorticosteroids, anti-leukotrienes, theophyllin, cromones, anti-cholinergics and p2 agonists form

10 drug categories that are currently being applied to I

allergic and non-allergic respiratory diseases such as asthma

I ma and chronic obstructive airways disease (COPD)

I act. Treatment guidelines for these diseases include- I

Both short and long-acting inhaled β2- I

I agonists. Short-acting P2 agonists that start quickly I

I are used for "rescue" trachea widening, I

I forms of lighting that work for a long time maintain lighting

I purchase and are used as maintenance therapy. I

I Windpipe dilation is mediated through agonism from I

The p2 adrenoceptor expressed on airway I

I smooth muscle cells, resulting in relaxation and I

I therefore trachea widening. Therefore, as a function I

Ional antagonists, p2 agonists the effects of all I

I prevent and reverse trachea constricting substances, I

Including leukotriene D4 (LTD4), acetylcholine, bradykinini

I ne, prostaglandins, histamine and endothelins. Because β2- I

I receptors are so widely distributed in the airway, I

P2 agonists also affect other types of cells that an I

I play a role in asthma. For example, it has been reported that I

32 agonists can stabilize load cells. The inhibition I

I of the release of trachea constricting substances can I

I are how P2 agonists induce trachea constriction I

I block by allergens, exercise and cold air. Furthermore I

I inhibit P2 agonists cholinergic neurotransmission in the I

Human airways, which can result in reduction

I third cholinergic reflex trachea constriction. I

I 1026329-3

In addition to the respiratory tract, it has also been established that β2 adrenoceptors are also expressed in other organs and tissues and therefore P2 agonists, such as those described in the present invention, may be useful in the treatment of other diseases such as, but not limited to to those of the nervous system, premature contractions, corigestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and in disorders where there is an advantage in reducing gastric acidity, in particular in gastric and gastric peptic ulceration.

Numerous P2 agonists, however, are limited in their use due to low selectivity or adverse side effects driven by high systemic exposure and primarily mediated by action on P2 adrenoceptors expressed outside the airways (muscle tremors, tachycardia, palpitations, restlessness) . Therefore, there is a need for improved resources in this category.

Accordingly, there is still a need for new p2 agonists that would have a suitable pharmacological profile, for example in terms of potency, selectivity, duration of action and / or pharmacodynamic properties. In this context, the present invention relates to new P2 agonists.

Various 2-amino-pyridine derivatives have already been synthesized. For example, U.S. Patent No. 4,358,455 describes compounds of random activity, either as β-adrenergic stimulants or as β-adrenergic blocking agents, having the formula:

OH

Thr.

ίΤν ^ Ν ^ ΥΥ ^ _ ij R (I YY “(Re)« 35 Η2Ν ^ νΓ 5 1026329 "i

4 I

wherein R 4 and R 5 are independently selected from H and (Ci-1

C 3) alkyl; Namely, Y can be a methylene group, R 6 becomes I

selected from H), OH, alkoxy, methylenedioxy, halogen or I

Alkyl; and n is 1 or 2. I

Another example relates to the patent application WO I

95/29259 those selective P3 agonists (with few βΐ and I

P2 activity) describes the formula: I

10 * 4 I

SO 4 CH 2 - R 11

<R1> b ^ T R1

R. I

I

wherein A can be a 6-membered heterocyclic ring with 1 L

up to 4 heteroatoms selected from O, S and N; R1 amino can I

and n can be 1; R2, R3 independently H or I

Can be (C1 -C10) alkyl; m is 0 or 1, and X is a methylene I

20 can be a group; R 4, R 5 can be H; Re is H or (C1 -C10) alkyl I

is; r is 0 to 3 and R 7 is a phenyl substituted 0 to 5 times

by numerous substituents (OH, oxo, halogen, CN I

etc.). I

Other 2-amino-pyridine derivatives are also described

25 in OS 5,714,506 as selective P3 agonists. These have I

more specifically the formula: I

OH r I

I HR, I

R »I

35 I

wherein R 1 can be amino; R2 is H or (Οι-ββ) alkyl; R3 and R4

independently can be H or {C 1 -C 12) alkyl; X a - (CH 2) n - I

1026329-I

5 can be a group with n selected from 1, 2 and 3; and Rsa and Rjb can be selected from -CONR2 R2, -0-CH2 -C0 NR2 R2r aryl, -CH2-alkoxy, -CH2-CONR2R2 where R2 is H or (Οι-β) alkyl.

However, none of the 2-amino-pyridine derivatives synthesized so far has shown selective P2 agonist activity, which allows them to be used as efficient drugs in the treatment of P2 mediated diseases and / or conditions. particularly allergic and non-allergic airway diseases or other diseases such as those previously cited.

The invention relates to the compounds of general formula (1): H x x j K x $ - *** ^ * (d h 2 n nk [fo 20 where the (CH 2) n C (= 0) Q 1 group in the meta or para is position, R1 and R2 are independently selected from H and C1 -C4 alkyl, n is 0, 1 or 2 and Q1 is a group selected from:

- * »X 'XJ

j = {

(CH a) p - / - R5 * - N - \ II \ - / W

\ R6 R6 rt r °.

1 and a group * -NR-Q 2 -A, wherein p is 1, 2 or 3, q is 1 or 2, Q 2 is a direct bond or a C 1 -C 4 alkylene optionally substituted by OH, RH, C 1 - C 4 is alkyl or phenyl optionally substituted by OH, and A is C 3 -C 7. is cycloalkyl, 1026329-

I 6 I

wherein said cycloalkyl is optionally bridged by one I

I or more carbon atoms, preferably 1 or 2 carbon atoms

1, tetrahydropyranyl, piperidinyl, tetrahydrothiopyra

Nylon, pyridyl or a group selected from: I

I 5 I

I R7 R R5 I

I wherein R3, R4, R5, R6 and R7 are the same or different I

I and each is independently selected from H, C1-4 alkyl, I

OR9, SR9, halogen, CF3, OCF3, (CH2) mCOOR9, SO2 NR8R9, CONReR9, I

NR 3 R 9, NHCOR 8, SO 2 (C 1 -C 4) alkyl and phenyl optionally substituted

Characterized by hydroxy or hydroxy (C 1 -C 4) alkyl; I

I wherein m is an integer selected from 0, 1 and 2, and R8 is I

And R9 are the same or different and become independent

Are selected from H or C 1 -C 4 alkyl and the * the attachment I

I represents a point on the carbonyl group; I

I or, if appropriate, the pharmaceutically acceptable salts I

I and / or isomers, tautomers, solvates or isotopic variations I

I 25 thereof. I

The compounds of the invention are selective I

I agonists of the P2 receptors, which are particularly useful I

I of P2 mediated diseases and / or disorders, by I

I exhibit strong force, especially if applied

I 30 served via the inhalation route. I

Preferably the term "selective" means that the ver

I bonds of formula (1) an agonist force for the β2-I

I receptor, which is at least about 50-fold higher I

I as for the P3 receptor and at least about 500-fold I

I 35 higher than for the βΐ receptor. I

The compounds of formula (1) preferably have I

I an agonist force for the β2 receptor, which is smaller I

I 1026329-7 than 10 nM as measured using the cell-based assay described herein.

In the general formula (1) above, C 1 -C 4 alkyl and C 1 -C 4 alkylene denote a straight-chain or branched group having 1, 2, 3 or 4 carbon atoms. This also applies if these substituents carry or exist as substituents of other radicals, for example in hydroxy (C1-C4) alkyl, O (C1-C4) alkyl residues, S- (C1-C4) alkyl residues, etc. For images of suitable (C 1 -C 4) alkyl radicals are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl ... hydroxy (C 1 -C 4) alkyl radicals are alkyl radicals substituted with a hydroxy (OH) substituent. According to a preferred embodiment of. In the aforementioned invention, such residues contain one hydroxy substituent which may be located at any position on the alkyl radical. Examples of suitable hydroxy (C 1 -C 4) alkyl radicals are hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, etc. ...

The term "C 3 -C 7 cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A preferred cycloalkyl group is cyclohexyl.

The C 3 -C 7 cycloalkyl, wherein 2 or more carbon atoms are optionally bridged by one or more carbon atoms include adamantanyl, bicyclo [3.1.1] heptane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane.

Finally, halo denotes a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine, in particular fluorine or chlorine.

In the following, the free bond on the phenyl group as in the structure below means that the phenyl may be substituted in the meta or para I position.

The 2-amino-pyridine derivatives of the formula (1) can be prepared by conventional procedures such as by the following illustrative methods wherein R1, R2, Q1 and n are as previously defined for the 2 -amino-pyridine derivatives of the formula (1) unless otherwise stated.

The 2-amino-pyridine derivatives of the formula (1) can be prepared by removing the protecting group (s) "Prot" from the compound of formula (2): Q1 (2) INJA1 4- (CH2) nw R1 R2

Prot-N N 'I wherein R 1, R 2, Q 1 and n are as previously described for I the 2-amino-pyridine derivatives of formula (1) and Prot an I suitable protecting group (or 2 suitable protecting I groups) for the amino pyridine, which includes but is not limited to tert-butoxycarbonyl, acyl or 2,5-dimethylpyrrole,

I methods known to those skilled in the art such as standard

I standard methodology for splitting off nitrogen

Screening groups as found in textbooks (e.g. I

I T.W. GREENE, Protective Groups in Organic Synthesis, A. I

I Wiley-Interscience Publication, 1981). I

The compound of formula (2) can be prepared by I

An acid of formula (3): I

I 1026329-35 9 f Η ls ί T A, 1 4 * (CH 2) n 5 A ^. R1 is R2

Prot-N N

*.

wherein Prot, R1, R2 and n are as previously defined, to be coupled with an amine of formula NRH-Q2-A (4.1), R3 R4 Γ V = / (CH2) p ^ A ^ R4> - ~ R5 HiN_VJLJL · 15 \ R5

HN— / \ I

R6 (4.2), R® (4.3), R3, R4

20 H2O-RS

t or R7 is R6 (4 × 4) wherein p, q, R3, R4, R5, R6 and R7 are as previously defined.

The coupling of the acid (3) to the amine (4.1), (4.2), (4.3) or - (4.4) is generally carried out in an excess of said amine, with a conventional coupling agent (e.g. 1 - (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or N, N'-dicyclohexylcarbodiimide), optionally in the presence of a catalyst (eg 1-hydroxybenzotriazole hydrate or 1-hydroxy-7-azabenzotriazole), and optionally in the presence of a tertiary amine base (e.g., N-methylmorpholine, triethylamine or N, N-35 diisopropylethylamine). The reaction can be undertaken in a suitable solution such as pyridine, Ν, Ν-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate, and at a temperature comprised between 10 ° C and 40 ° C ( room temperature).

Said (4.1), (4.2), (4.3) or (4.4) is either commercially available or can be prepared using conventional methods well known to those skilled in the art.

I (e.g., acylation, sulfonylation, reduction, oxidation, alkyl

education, protection, protection, etc.) from commercial I

Available material. I

The acid of formula (3) can be prepared from the I

Corresponding ester of formula (5): I

I OH I

I Y H jf

I / ^ ORa (5) I

I T λ, I

I is A 1, ^ 1 r1 r2

Prot-N N

I wherein Prot, R1, R2, Ra and n are as previously defined

According to any method well known to those skilled in the art, I

Prepare an acid from an ester. I

In a typical procedure, the hydrolysis of the I

I ester to give an acid undertaken according to each of the art

A well-known method of producing an acid from an ester

Without modifying the rest of the molecule

I run. For example, the ester can be hydrolyzed by I

Treatment with aqueous acid or base (e.g., hydrogen chloride)

Irid, potassium hydroxide, sodium hydroxide or lithium hydroxide

De), optionally in the presence of a co-solvent

I (e.g. tetrahydrofuran / 1,4-dioxane) at a temperature om

I 30 barrel between 20 ° C and 100 ° C, for a period of 1 to I

I 40 hours. I

The ester of formula (5) can be prepared according to I

I different routes depending on the choice of R1 and R2. I

I When R 1 is hydrogen, R 2 is (C 1 -C 4) alkyl and n is difference-1

If the value of the ester is of 0, then the ester of formula (5) can be used

Prepared by reaction of an amine of formula (6): I

I 1026329-11

OH

2 (6) 5 D.

Prot-N N

with an excess of a ketone of the formula (7): 10 @ +> Y ^ fV (CHAA0R3 171

O

Wherein Prot, R2, Ra and n are as previously defined, to form an intermediate compound which is reduced by a suitable reducing agent (eg sodium cyanoborohydride of formula NaCN (BH) 3 or sodium triacetoxyborohydride of formula Na (0Ac) 3BH ), optionally in the presence of acetic acid. The reaction is generally carried out in a suitable solvent such as tetrahydrofuran or dichloromethane, at a temperature comprised between 20 ° C and 80 ° C for 3 to 72 hours, and gives the compound of formula (5) as a mixture of diast -25 romeres. According to another alternative, the reduction can be carried out in the presence of a drying agent such as molecular sieves or magnesium sulfate.

The amine of formula (6) can be prepared from a 2-amino-5-bromo-pyridine as described in EP 3078 924 or WO 99/32475.

Alternatively, the ester of formula (5) can be prepared according to scheme 1 as follows: 1026329-12

Schedule 1

I 2 O fc O

H Y R a R b I (7) (8):

I Ji I

10 10 10 (10) „-H-XJ- (CH =») 0 Ra

Prot-N N

(9)

I, -XVyv X

15 (I T A B J-PUr 2 OR 3 (5) R 2 R 1

Prot-N N

I (R15 H) I wherein n, Ra and Prot are as previously defined, and I Rb and Rc represent all suitable substituents such that HNRbRc is a chiral amine (e.g., Rb can be hydrogen and Rc can be an α-methylbenzyl group ) and the bonds between n and Rb and N and Rc can easily be cleaved to give the free amine of formula (9).

In a typical procedure, the ketone of formula (7) is reacted with a suitable chiral non-racemic amine HNRbRc (eg α-methylbenzylamine or any other commercially available chiral non-racemic amine) to to form a chiral intermediate, which is reduced with a suitable reducing agent (eg sodium cyanoborohydride of formula NaCN (BH) 3 or sodium triacetate oxyborohydride of formula Na (0Ac) 3BH) optionally in the presence of sodium acetate or acetic acid, and also possibly in the presence of a drying agent (eg molecular sieves, magnesium sulfate) as previously described. The resulting product is then converted to the hydrochloride salt and selectively crystallized from a suitable solvent or mixture of solvents (eg isopropanol, ethanol, methanol, diisopropyl ether or diisopropyl ether / methanol) to purify the diastereomerically product, duet of formula (8), or the. enantiomer thereof, if the opposite enantiomers of the amine HNRbRc are used.

The protected amine of formula (8) is then split to give the corresponding free amine of formula (9) using standard methodology for cleaving nitrogen protecting groups, such as those found in the textbook (see, for example, TW Greene, Protective Groups in Organic Synthesis, A. Wiley-Inter-science Publication, 1981). If an α-methylbenzylamine is used, the cleavage can be carried out with the aid of ammonium formate and palladium hydroxide on carbon of the formula Pd (OH) 2 / C as a catalyst.

Said amine of formula (9) is then reacted with an epoxide of formula (10) in a suitable solvent or mixture of solvents (e.g. di-20 methylsulfoxide / toluene), at a temperature comprised between 20 ° C and 80 ° C and optionally in the presence of a catalyst for 8 to 40 hours to give the ester of formula (5).

The epoxide of formula (10) can be prepared from a 2-amino-5-bromo-pyridine as described in EP 1,078,924 or WO 99/32475.

The ketone of formula (7) described above can be prepared by enolate arylation of an aryl halide of formula (11):

30 O

wherein Ra and n are as previously defined and halo represents a halogen atom which includes, but is not limited to, fluorine, chlorine and bromine.

I In a typical procedure, the aryl halide of formula (11) is reacted with a tin olate generated in I by treatment of a vinyl acetate I (e.g., isoprenyl acetate with tri-n-butyl tin methoxide of formula Bu3 SnOMe) in the presence of a suitable palladium. Iodium catalyst (palladium acetate / tri-ortho-tolylphosphine of formula Pd (OAc) 2 / P (o-Tol) 3) in a non-polar solvent (eg toluene, benzene, hexane). Preferably, the reaction is carried out at a temperature comprised between 80 ° C and 110 ° C for 6 to 16 hours.

The aryl halide of formula (11) can be prepared by esterification of the corresponding acid of formula I (12): 1 ha> Y (cH 2) A ° H <12> 20 1 I 1026329 - wherein halo is as before defined by any method well known to those skilled in the art to prepare an ester from an acid without modifying the remainder of the molecule.

In a typical procedure, the acid of formula (12) is reacted with an alcoholic solvent of formula RaOH, where Ra is as previously defined, in the presence of an acid such as hydrochloric acid at a temperature between 10 ° C and 40 ° C ( room temperature) for 8 to 16 hours.

In another alternative, the acid of formula (12) is reacted with a bromoalkyl of formula RaBr in the presence of a suitable base such as calcium carbonate, in a suitable organic solvent (e.g.

15 Ν, Ν-dimethylformamide, tetrahydrofuran) at a temperature and for a time as mentioned above.

The acid of formula (12) is either a commercial product or it can be prepared by conventional procedures well known to those skilled in the art.

If R 1 and R 2 are both different from hydrogen and n is different from 0, the ester of formula (5) can be prepared according to scheme 2 as follows: Scheme 2 ΎΚ> "- 7ΓΟ" 15 1 'VX0 * <15) (16) 20

_Vi ^ i_ X

p H1 4- (CH 2) n ^ ORa

Prat — N N

Pret (10) (5) wherein R1, R2, Ra and Prot are as previously defined. In a typical procedure, the halogen ketone of formula 13) is reacted with an "activated" alkyl (organometallic alkyl such as R2 MgBr, R2 MgCl or R2 Li) to give the corresponding tertiary alcohol of formula (14). This organometallic addition is generally undertaken in a suitable solvent such as tetrahydrofuran, ether, cyclohexane or 1,4-dioxane, at a temperature comprised between 10 ° C and 40 ° C (room temperature) for 1 to 24 hours.

Said tertiary alcohol of formula (14) is then treated with an alkyl nitrile (eg acetonitrile, chloroacetonitrile) in the presence of an acid (eg sulfuric acid, acetic acid) to give a protected intermediate product which in turn, it is cleaved using standard methodology to cleave a nitrogen protecting group, such as those mentioned in textbooks, to give the amine of formula (15).

The amine of formula (15) is then converted to the boronic acid ester by treatment with a suitable boron source (e.g. pinacolborane, bis (pinacolato) dibore) in the presence of a suitable palladium catalyst (e.g.

Palladium (II) acetate / tri-ortho-tolylphosphine of formula I Pd (OAc) 2 / P (o-tol) 3 or (diphenylphosphino) ferrocenylpalladium-I (II) chloride of formula dppfPdCl 2). The response is in.

generally undertaken in a suitable solvent such as dimethyl sulfoxide or toluene, optionally in the presence of a base (e.g. potassium acetate), at a temperature comprised between 60 ° C and 110 ° C for a period of 4 to 20 hours, The intermediate boronic acid ester is then coupled with ethyl bromoacetate in the presence of a suitable palladium catalyst (e.g. tetrakis (triphenylphosphine) palladium (0) of formula Pd (PPh3) 4, palladium (II) acetate / tri-ortho-tolylphosphine with formula Pd (OAc) 2 / P (o-tol) 3 or (diphenylphosphino) ferrocenyl palladium (II) chloride of formula dppfPdCl 3) to give the compound of formula (16).

The compound of formula (5) is finally obtained by reacting the compound of formula (16) with the epoxide of formula (10) as previously described.

The compound of formula (13) is either commercial or can be easily prepared from commercial compounds using conventional procedures well known to those skilled in the art.

Alternatively, the amine of formula (16) can be prepared according to Scheme 3 as follows:

Schedule 3

5 RaO. ^ ^ ^ _ ^ ^ pViCHJ ^ OH

Y] 0 Hch 2) OH OH R 1 -1 (17). (18) - ^ X ^ Y ^ V (CH 2) 4 ORa 10 R 1 R 2 (16) wherein R 1, R 2 and R a are as previously defined.

In a typical procedure, the ester of formula (17) is reacted with an "activated" alkyl (organometallic alkyl such as R2 MgBr, R2 MgCl or R2 Li) to give the corresponding tertiary alcohol of formula (18) using the method described above.

Said tertiary alcohol of formula (17) is then treated with an alkyl nitrile (eg acetonitrile, chloroacetonitrile) in the presence of an acid (eg sulfuric acid, acetic acid) to give a protected intermediate which in turn is split with the aid of 25 of standard methodology for splitting off a nitrogen protecting group such as those mentioned in textbooks. The resulting amino acid is then esterified by the method described herein to give the amine of formula (16).

The compound of formula (17) is either commercial or can be easily prepared from commercial compounds using conventional procedures well known to those skilled in the art.

If n is 0, then the amine of formula 35 (16) can be prepared according to the following scheme: 1026329-I 18 I Scheme 4 - I 5 T UB '- Λ * u ^ Br, - I (19) (20> I ίο ¥) m? I WW \ J ~ "* R" R2 L ^ \> Ra '(21) (16) wherein R1, R2 and Ra are as previously defined.

In a typical procedure, the ester of formula I (19) is reacted with an "activated" alkyl (organometallic alkyl such as R2 MgBr, R2 MgCl or R2 Li) to use the corresponding tertiary alcohol of formula (20). Using the method described above.

Said tertiary alcohol of formula (20) is then treated with an alkyl nitrile (eg acetonitrile, chloroacetonitrile) in the presence of an acid I (eg sulfuric acid, acetic acid) to give a protected intermediate product that is on its in turn is split using standard I methodology for splitting off nitrogen protecting group such as those mentioned in textbooks to give the bromoamine (21).

The resulting bromamine (21) is treated with a suitable palladium catalyst (eg [1,1'-bis (diphenylphosphino) ferrocene] dichloro palladium (II) under an atmosphere of carbon monoxide using RaOH as a solvent I del (e.g. MeOH, EtOH) at elevated temperature (100 ° C) and I pressure (100 psi) to give the ester of formula (16).

The compound of formula (19) is either commercial or can be easily prepared from commercial compounds using conventional procedures well known to those skilled in the art.

Alternatively, where both R1 and R2 are H, the amine of formula (16) can be prepared according to scheme 5 as follows:

Scheme 5 X-V ^ T ^ - (CH 2) h ^ sOR 8 ^ (20) (17) 15 ^

JL

-V -ORa (16) wherein Ra is as previously defined.

In a typical procedure, the ester of formula (17) is reduced with a reducing agent (such as L1 AlH3) to give the corresponding primary alcohol of formula (20) by the method described above.

Said tertiary alcohol of formula (20) is then treated to give an activating group (G) (halogen, mesylate, tosylate) using standard methodology for alcohol activation such as those mentioned in textbooks. The resulting activating group is then replaced by a nitrogen-containing group (such as azide, phthalamide) using standard methodology for nucleophilic replacements such as those mentioned in textbooks. The amine is then released by hydrolysis (hydroxide, hydrazine) or reduction (hydrogenation, reducing agent such as L1 AlH4) of the nitrogen-containing group to give the amine of formula (16).

All of the above reactions and the preparations of novel starting materials used in the foregoing processes are conventional and suitable reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired product. Products will be well known to those skilled in the art with reference to literature precedents and the examples and preparations thereof.

For some of the steps of the above-described method of preparation of the 2-amino-pyridine derivatives of formula (1), it may be necessary to react the potential reactive functions that one does not wish to react to. to protect, and to subsequently split off said protecting groups. In such a case, any compatible protective residue can be used.

In particular, methods of protection and protection such as those described T.W. GREENE (Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication, 1981) or by McOMIE (Protective Groups in Organic Chemistry, Plenum Press, 1973).

The 2-amino-pyridine derivatives of formula I (1) as well as intermediates for their preparation can also be purified by various well-known methods, such as, for example, crystallization or chromatography.

Compounds of formula (1) wherein · η is 1 or 2, Q 1 is a group * -NH-Q 2 -A, wherein Q 2 is a C 1 -C 4 alkylene and A is a group I R 3 R 4 I [- R 5 I r Xr6 I 1026329-35 21.

wherein R 3, R 4, R 5, R 6, and R 7 are 21 as defined above, are particularly preferred. The following substituents are generally preferred: R1 is H and R2 is C1 -C1 alkyl, more preferably CH3 or R2 and R2 are the same or different and are selected from C1 -C4 alkyl, more preferably R1 and R2 Both CH3 and / or, n is 1 and / or, Q2 is selected from -CH2-, - (CH2) 2- / ((CH2) 3- and 10 -CH (CH3) -, more preferably Q2 is -CH2 -, and / or A is a group of formula: R3, R4, R5, R7, R3 where R3, R4, R5, R6 and R7 are the same or different and are selected from H, C1 -C4 alkyl, OR9, C 1, F, CF 3, OCF 3, COOR 9, C (= O) NR 8 R 9, SO 2 NR 8 R 9, provided that at least 2 of R 3 to R 7 are equal to H, wherein R 8 and R 9 are the same or different and are selected from H or C1 -C4 alkyl.

Preferably, A is a group of formula: R 3, R 4

|RS

R 6 where R 3, R 4, R 5, R 6 and R 7 are the same or different and are selected from H, CH 3, OH, OCH 3, OCH 2 CH 3, Cl, F, CF 3, OCF 3, COOH, SO 2 NH 2, provided that at least 2 of R3 to R7 are H.

Preferably A is a group of formula: 1026329-

22 I

R3 R4 I

I - \ / - R5 I

4 «I

wherein R3, R4, R5, R6 and R7 are the same or different I

and are selected from H, CH 3, OH, OCH 3, OCH 2 CH 3, Cl, F, CF 3, I

OCF 3, COOH, SO 2 NH 2, provided that at least 3 of I

R3 to R7 are equal to Η. I

Preferably A is a group of formula: I

R8 R4 I

R7 R® I

Wherein R 3, R 4, R 5, R 6, and R 7 are selected from H, CH 3, δ H, I

Cl, OCH 2 CH 3, provided that at least 3 from R 3 to I

R7 is equal to Η. I

Preferably A is a group of formula: I

R 1 / R 4 I

- RS 1

R7 V1

30 I

wherein at least one of R3, R4, R5, R6 and R7 is different I

then hydrogen. I

other preferred compounds are those in which η 1 or I

2 and Q is I

35 I

1026329-5 I

R 3 is R 4, R 5, R 4, R 5 and R 6 are the same or different and are selected from H, C 1 -C 4 alkyl, OR 9, SR 9, halogen, CF 3, OCF 3 , COOR9, SO2 NR8 R9, CONRbR9, NRbR9, NHCOR9, provided that at least 2 of R3 to R6 are H, wherein R8 and R9 are the same or different and are selected from H or C1 -C4 alkyl.

Preferably, Q1 is R3, R4 - - (/ J {'R *

"-" V

Wherein R 3, R 4, R 5 and R 6 are the same or different and are selected from H and OR 9, provided that at least 2 of R 3 to R 6 are H; Wherein R 9 is selected from H or C 1 -C 4 alkyl.

Other preferred compounds are those where η is 1 or 2 and Q1

"TtCO

is.

Other preferred compounds are those in which η is 1 or 2 and Q1 is a group * -NH-Q2-A, wherein Q2 is a C1-G4 alkylene and A is a pyridin-2-yl.

1026329-124

Other preferred compounds are those in which η 1 or I

I is 2 and Q1 is a group * -NH-Q2-A, where Q2 is a C1-C4 I

I is alkylene and A is naphthyl. I

Other preferred compounds are those in which η 1 or I

I 5 is 2 and Q 1 is a group * -NH-Q 2 -A, where Q 2 is a C 1 -C 4

I is alkylene and A is C3 -C7 cycloalkyl, wherein said cy I

Cloalkyl is optionally bridged by one or more carbon

I atoms. Preferably A is cyclohexyl, cycloheptyl or ada-I

mantanyl. I

Other preferred compounds are those in which η 1 or I

I is 2 and Q1 is a group * -NH-Q2-A, where Q2 is a C1 -C * I

I is alkylene and A is naphthyl substituted with OH. I

Other preferred compounds are those of formula

I (1), wherein n is 0 or 1 and Q1 is a group of formula: I

I 15 I R3 R4 03 I \. / R9 R * I (CH *) p y} R5 - R8 I 20 V / R6 I. / \ IR®, or R7 -R6 I wherein p is 2 or 3, q is 2, R3, R4, R5, R6 and R7 are the same I or different and are selected from H and OH, provided that at least at least one of R3, R4, R5, R6 and R7 is OH.

Other preferred compounds are those of formula (1) I wherein n is 0 or 1, R 1 is H or C 1 -C 4 alkyl, R 2 is C 1 -C 4 alkyl I, and Q 1 is a group * -NR-Q 2 -A wherein A is formula R3, R4, R3, R4, R4, R4, R4, R4, R5, R6, and R7 are as previously defined.

The following substituents are generally preferred:. .

5- R1 is H and R2 is C1 -C4 alkyl, more preferably CH3 or R1 and R2 are the same or different and are selected from C1 -C4 alkyl, more preferably R1 and R2 are both CH3 and / or, R is selected from H, CH 3, CH 2 CH 3 and phenyl substituted by OH, and / or Q 2 is a direct bond or is selected from -CH 2 -, - (CH 2) 2 -, - (CH 2) - -, -CH 2 -C ( CH 3) 2, and -CH 2 -CH (OH) and / or A is a group of formula: R 5 wherein R 3, R 4, R 5, R 6 and R 7 are the same or different and are selected from H, C1 -C4 alkyl, OR9, C1, F, CF3, CO-OR9, SO2 (C1 -C4) alkyl, and phenyl substituted by OH or hydroxy (C1 -C4) alkyl, provided that at least 2 of R3 to R7 are H, wherein R® and R9 are the same or different and are selected from H or C1 -C4 alkyl.

Preferably, A has formula R3> R4> R4

R7 V

Wherein R3, R4, R5, R6 and R7 are the same or different and are selected from H, CH3, C (CH3) 3, OH, OCH3, OCH2 CH3, 1026329-

I 26 I

I is Cl, F CF 3, COOCH 3, SO 2 CH 2 CH 3, and phenyl substituted by I

I OH or by -CH 2 OH, with the proviso that at least 2 I

I from R3 to R7 are equal to Η. I

The compounds with the I are particularly preferred

Formula (1) as described in the Examples section here

I na, i.e.: I

2- (3 - {(2 R) -2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-1

Ethylamino] -propyl} -phenyl) -N-benzyl-acetamide, I

2- (3 - {(2 R) -2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-1

Ethylamino] -propyl} -phenyl) -N- (2-methoxy-benzyl) -acetate

I amide, I

I 2— (3— {(2 R) -2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-1

Ethylamino] -propyl) -phenyl) -N- (2-ethoxy-benzyl) -acetamide, I

2- (3 - {(2 R) -2-t (2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-1

Ethylamino] -propyl] -phenyl) -N- (3-phenyl-propyl) -acetamide, I

2- (3 - {(2 R) -2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-1

Ethylamino] -propyl] -phenyl) -N-phenethyl-acetamide, I

2- (3 - {(2 R) -2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-1

Ethylamino] -propyl} -phenyl} -N- (3,4-dimethyl-benzyl) -I

Acetamide, I

2- (3 - {(2 R) -2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-1

Ethylamino] -propyl] -phenyl) -N-indan-2-yl-acetamide, I

2- (3 - {(2 R) -2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-1

Ethylamino] -propyl-phenyl) -N- (3,4-dichloro-benzyl) -. I

Acetamide, I

2- (3- {2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethyl] -1

Amino] -propyl} -phenyl) -N- (4-hydroxy-3-methoxy-benzyl) -1

Acetamide, I

2- (4- {2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-1

Ethylamino] -2-methyl-propyl) -phenyl) -N- (3-methoxy-be.nzyl) -I

Acetamide, I

2- (4- {2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethyl] -1

Amino] -2-methyl-propyl) -phenyl) -N- (2,6-dimethoxy-benzyl) -1

Acetamide, I

2- (3- {2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethyl-amino] -2-methyl-propyl) -phenyl) - N- (4-sulfamoyl-benzyl) -acetamide, 2 - (3- {2- [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethyl-5-amino] -2 -methyl-propyl) -phenyl) -N- (2-ethoxy-benzyl) -acetamide, 2 - (3 - {2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2- hydroxy-ethyl-amino] -2-methyl-propyl} -phenyl) -N-indan-2-yl-acetamide, 2 - <3 - {2 - [(2R) -2- (6-Amino-pyridin-3) -yl) -2-hydroxy-ethyl-10 amino] -2-methyl-propyl) -phenyl) -N-benzyl-acetamide, 2 - (3 - {2 - f (2R) -2 - (6-amino) pyridin-3-yl) -2-hydroxy-ethyl-amino] -2-methyl-propyl) -phenyl) -N-phenethyl-acetamide, 2- (3- {2 - [(2R) -2- (6- Amino-pyridin-3-yl) -2-hydroxy-ethyl-amino] -2-methyl-propyl} -phenyl) -N- (3-phenyl-propyl) -acet-15 amide, 2- (3- {2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethyl-amino] -2-methyl-propyl} -phenyl) -N- (3,5-dichloro-benzyl) -acetamide, 2- (3 - {2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethyl-20 amino] -2-methyl-propyl) -phenyl) - N- (3,4-dimethyl-benzyl) -acetamide, 2 - (3 - {2 - t (2R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethyl-amino] -2-methyl-propyl) -phenyl) -N- (3,4-dichloro-benzyl) -acetamide 2- {3 - {2 - [(2R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethyl-amino) -propyl) -phenyl) -N- (2-fluoro) -5-trifluoromethyl-benzyl) -acetamide, 2 - (3 - {2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethyl-amino] -propyl) -phenyl ) - N - (3-trifluoromethoxy-benzyl) -acet-30-amide, 2- (3- {2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethyl-) amino) -propyl) -phenyl) -N- (3-fluoro-4-trifluoromethyl-benzyl) -acetamide, 2 - (3 - {2 - [(2R) -2- (6-Amino-pyridin-3-yl) ) -2-hydroxy-ethyl-35 amino] -propyl) -phenyl) -N- (3,4,5-trimethoxy-benzyl) -acetamide, 1026329-

28 I

- (3- {2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxyethyl] -1

amino] -propyl} -phenyl) -N- (4-trifluoromethoxy-benzyl) -acetate-I

amide, I

2- (3- {2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxyethyl] -1

5 amino] -propyl} -phenyl) -N- (4-fluoro-2-trifluoromethyl-benzyl) -1

acetamide, I

2- {3 - {2 - [(2R) -2- (6-Amino-pyridin-3-yl) -2-hydroxyethyl] -1

amino] -propyl} -phenyl) -N- (5-fluoro-2-trifluoromethyl-benzyl) -1

acetamide, I

2- (3 - {(2 R) -2- [2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

amino] -2-methylpropyl} phenyl) -N- (4'-hydroxybiphenyl-3-)

ylmethyl) acetamide, I

2- (3 - {(2 R) -2- [2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

amino] -2-methylpropyl] phenyl) -N- (4'-hydroxybiphenyl-4- I

Ylmethyl) acetamide, I

2 - {3 - {(2 R) -2 - [(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-1

ethylamino] propyl} phenyl) -N- (4'-hydroxybiphenyl-3-ylmethyl) -1

acetamide, I

2- (3 - {(2 R) -2 - [(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

Amino] propyl] phenyl) -N- (4-hydroxynaphthalen-1-ylmethyl) -1

acetamide, I

3- {2 - [(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethylamino] -2-. I

methylpropyl} -N- (4f-hydroxybiphenyl-3-ylmethyl) benzamide, I

3 - {(2R) -2- [2- (6-Amino-pyridin-3-yl) -2-hydroxyethylamino] -1

2-methyl-propyl} -N- [2- (4-hydroxy-phenyl) -2-methyl-propyl] -1

benzamide, I

3- {2 - [(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethylamino] -2- I

methylpropyl} -N- [2- (4-hydroxy-2,5-dimethylphenyl) ethyl] -1

benzamide, I

3- {2 - [(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethylamino] -2- I

methylpropyl} -N- [2- (4-hydroxy-2,3-dimethylphenyl) ethyl] -1

benzamide, I

3- {2 - [(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethylamino] -2- I

methylpropyl) -N- [2- (4-hydroxy-2-methylphenyl) ethyl] benzyl

Amide, I

1026329-I

29 3 - {(2 R) -2 - [(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl-amino] propyl} -N- [2- (4-hydroxy-2,5-) dimethylphenyl) ethyl] benzamide, 3 - {(2 R) -2 - [(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl-5 amino] propyl] -N- [2- (4 -hydroxy-2,3-dimethylphenyl) ethyl] benzamide, 3 - {(2 R) -2 - [(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl-amino] propyl} -N - [2- (4-hydroxy-2-methylphenyl) ethyl] -benzamide, 2- [3- {2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] - amino} -2-methyl-propyl) phenyl] -N- (3-hydroxy-4-methoxy-phenyl) acetamide, 2- [3- (2 - {[(2 R) -2- (6-Aminopyridin-3-) yl) -2-hydroxyethyl] -amino} -2-methyl-propyl) phenyl] -N- (3-hydroxy-phenyl) acet-15 amide, 2- [3- (2 - {[(2R) -2-) (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino} -2-methyl-propyl) phenyl] -N- (2-chloro-4-hydroxy-phenyl) acetamide, 2- [3- (2- {[(2R) -2- {6-Aminopyridin-3-yl) -2-hydroxyethyl] -20 amino} -2-methyl-propyl) phenyl] -N- (4-hydroxy-3-methoxy-benzyl) acetamide , 2— [3 - (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino] -2-methyl-propyl) phenyl] -N-15- (ethylsulfonyl) -2-hydroxyphenyl] a ceetamide, 2- [3- (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] amino] -2-methyl-propyl) phenyl] -N- (2 -hydroxy-5-methyl-phenyl) acetamide, 2 - [3 - (2-I [(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino} -2-methyl-propyl) ) phenyl] - N - (5-chloro-2-hydroxy-benzyl) acetamide, 2- [3- (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino} -2-methyl-propyl) phenyl] -N- (4-hydroxy-1,1'-biphenyl-3-yl) acetamide, 2- [3- (2 - {[(2R) -2- ( 6-Aminopyridin-3-yl) -2-hydroxyethyl] -35 amino] -2-methyl-propyl) phenyl] -N- [2-hydroxy-2- (3-hydroxy-phenyl) ethyl] -N-methyl- acetamide, 1026329-

30 I

2- [3- (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1)

amino) -2-methyl-propyl) phenyl] -N-ethyl-N- (3-hydroxy-1

phenyl) acetamide, I

2- [3- (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1)

5 amino} -2-methyl-propyl) phenyl] -N- [2- (3-ethoxy-4-hydroxy-1)

phenyl) ethyl acetamide, I

2- [3- (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl) -1

amino) -2-methyl-propyl) phenyl] -N - {[4 '- (hydroxymethyl) -1,1'-1

biphenyl-3-yl] methyl] acetamide, I

2- [3- (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1)

amino) -2-methyl-propyl) phenyl] -N- (2,4-dichloro-6-hydroxy-1)

benzyl acetamide, I

2- [3- (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1)

amino) -2-methyl-propyl) phenyl] -N - [(3-fluoro-4'-hydroxy-1,1'-1

Biphenyl-4-yl) methyl] acetamide, I

2- [3- (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1)

amino] -2-methyl-propyl) phenyl] -N - [(4'-hydroxy-3-methyl-1

1,1'-biphenyl-4-yl) methyl] acetamide, I

2- [3- (2- {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1)

20 amino) -2-methyl-propyl) phenyl] -N- (2-chloro-5-hydroxy-1)

benzyl) -N-ethylacetamide, I

2- [3- (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1)

amino] -2-methyl-propyl) phenyl] -N - [(2'-hydroxy-1,1 # -biphenyl-1)

2-yl) methyl] acetamide, I

2- [3- (2 - {[(2 R) -2- (6-phenopyridin-3-yl) -2-hydroxyethyl] -1)

amino] -2-methyl-propyl) phenyl] -N- [3-hydroxy-5- (trifluoro-1

methyl) benzyl] -N-methylacetamide, I

2- [3- (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1)

amino} -2-methyl-propyl) phenyl] -N- {3-chloro-5-hydroxy-1

Benzyl) -N-ethyl acetamide, I

2— [3— (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1)

amino] -2-methyl-propyl) phenyl] -N- (3-chloro-5-hydroxy-1)

benzyl acetamide, I

2- [3- (2- {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1)

35 amino] -2-methyl-propyl) phenyl] -N- (4-hydroxy-3,5-dimethyl-1)

benzyl acetamide, I

1026329-I

31 2 - [3- (2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1-amino) -2-methyl-propyl) phenyl] -N- [2- (2-hydroxyphenyl) ethyl] -acetamide, 2- [3- (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -5 amino} -2-methyl-propyl ) phenyl] -N-benzyl-N- (4-hydroxyphenyl) -acetamide, 2— [3 - (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino) } -2-methyl-propyl) phenyl] -N- [2- (4-hydroxyphenyl) -ethyl] acetamide, 2- [3- (2 - {[(2 R) -2- (6-Aminopyridin-3-)] yl) -2-hydroxyethyl] -amino} -2-methyl-propyl) phenyl] -N- (4-hydroxybenzyl) acetamide, 2- [3- (2 - {[(2R) -2- (6-Aminopyridin) 3-yl) -2-hydroxyethyl] -amino) -2-methyl-propyl) phenyl] -N- (2-hydroxybenzyl) acet-15 amide, 2- (3- (2 - ([(2R) -2-) (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino) -2-methyl-propyl) phenyl] -N- (3-hydroxybenzyl) acetamide, 2- [3- (2 - {[(2R) - 2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -20 amino) -2-methyl-propyl) phenyl] -N- [2- (3-hydroxyphenyl) -ethyl] acetamide, 2- [3- (2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino} -2-methyl-propyl) phenyl] -N- [2- (4-hydroxy-3-) methoxy-phenyl) et hyl] acetamide, Methyl 4 - ({[3- (2 - {[(2 R) -2- (6-aminopyridin-3-yl) -2-hydroxyethyl] -amino) -2-methyl-propyl) phenyl ] acetyl) amino) -3-hydroxybenzoate, 2- [3- (2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino} -2-methyl-propyl) phenyl] -N- (5-tert-butyl-2-hydroxy-phenyl) acetamide, 2- [3- (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2- hydroxyethyl] -amino) -2-methyl-propyl) phenyl] -N- (3-hydroxy-4-methyl-phenyl) acetamide, 2- [3 - ((2R) -2 - {[(2R) -2-) (6-Aminopyridin-3-yl) -2-hydroxy-ethyl-amino-propyl) -phenyl] -N- [2- (4-hydroxy-phenyl) -ethyl] -acetamide, 1026329-

32 I

2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy] -1

ethyl] aminopropyl) phenyl] -N- (4-hydroxybenzyl) acetamide, I

2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy] -1

ethyl] amino} propyl) phenyl] -N- (2-hydroxybenzyl) acetamide, I

5 2— [3 - {(2 R) -2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxy]

ethyl] aminopropyl) phenyl] -N- (3-hydroxybenzyl) acetamide, I

2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy] -1

ethyl] amino} propyl) phenyl] -N- (2- (3-hydroxyphenyl) ethyl] -1

acetamide, I

2- (3 - ((2R) -2 - {((2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-1

ethyl] amino-propyl) phenyl] -N- [2- (4-hydroxy-3-methoxyphenyl) -1

ethyl] acetamide, I

2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy] -1

ethyl] amino} propyl) phenyl] -N- (5-tert-butyl-2-hydroxyphenyl) -1

Acetamide, I

2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy] -1

ethyl] aminopropyl) phenyl] -N- (3-hydroxy-4-methylphenyl) -1

acetamide, I

2- (3- ((2R) -2- {[(2R) -2- (6-Amiriopyridin-3-yl) -2-hydroxy-1

Ethyl] amino-propyl) phenyl] -N- (3-hydroxy-4-methoxyphenyl) -1

acetamide, I

2- (3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-1

ethyl] amino} propyl) phenyl] -N- {4-hydroxy-3-methoxybenzyl) -1

acetamide, I

2- (3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-1

ethyl] aminopropyl) phenyl] -N- [5- (ethylsulfonyl) -2-hydroxy-1

phenyl] acetamide, I

2- (3- ((2R) -2 - {((2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-1

ethyl] aminopropyl) phenyl] -N- (2-hydroxy-5-methylphenyl) -1

Acetamide, I

2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy] -1

ethyl] aminopropyl) phenyl] -N- (3-hydroxy-2-methylphenyl) -1

acetamide, I

2- (3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-1

Ethyl] amino-propyl) phenyl] -N- (5-chloro-2-hydroxybenzyl) -1

acetamide, I

1026329-33 2- (3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino-propyl) -phenyl] -N- [2-hydroxy -2- (3-hydroxyphenyl) -ethyl] -N-methyl-acetamide, 2- (3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2- hydroxy-5-ethyl] amino} propyl) phenyl] -N- [2- (3-ethoxy-4-hydroxyphenyl) -ethyl] acetamide, 2- (3 - ((2R) -2 - {[(2R) -2 - (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] amino-propyl) phenyl] -N- [2- (3-hydroxy-4-methoxy-phenyl) ethyl] acetamide, 2- (3 - ((- 2R) -2 - ([(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] aminopropyl) phenyl] -N-ethyl-N- [2- (4-hydroxyphenyl) -ethyl ] acetamide, 2- (3 - ((2R) -2 - ([(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino-propyl) -phenyl) -N- (2-chloro) -4-hydroxybenzyl) -N-15 ethyl acetamide.

2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] amino] propyl) phenyl] -N- (5-hydroxy-1, 2,3,4-tetrahydro-naphthalen-1-yl) acetamide, 2- (3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy- Ethyl] amino-propyl) phenyl] -N- (4-hydroxyphenyl) acetamide, 2- (3 - ((2R) -2 - {((2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy -ethyl] amino-propyl) phenyl] -N- (4- (4-hydroxyphenyl) butyl] -acetamide, 2- (3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-) yl) -2-hydroxy-ethyl] amino-propyl) phenyl} -N - ((4-hydroxy-1,1'-biphenyl-4-yl) methyl] acetamide, 2- (3 - ((2R) -2) - {((2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] aminopropyl) phenyl] -N - {[A '- (hydroxymethyl) -1,1'-biphenyl-3- yl] methyl} acetamide, 2- (3 - ((2R) -2 - {((2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] amino-propyl) phenyl] -N- (2,4-dichloro-6-hydroxy-benzyl) acetamide, 2- (3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl ] aminopropyl) phenyl] -N - [(3-fluoro-4f-hydroxy-1,1'-35-biphenyl-4-yl) methyl] acetamide, 1026329 2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] a minoypropyl) phenyl] -N - [(4'-hydroxy-3-methyl-1,1'-biphenyl-4-yl) methyl] acetamide, 2- [3 - ((2R) -2 - {[(( 2R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethyl] -amino} -propyl) -phenyl] -N- (2-chloro-5-hydroxybenzyl) -N-1-ethylacetamide, 2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] amino} propyl) phenyl] -N - [(2'-hydroxy -1,1'-biphenyl-2-yl) methyl] acetamide, 10 2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2 -hydroxy-ethyl] amino] propyl) phenyl] -N- [3-hydroxy-5- (trifluoromethyl) benzyl] -N-methylacetamide, 1- 2- [3 - ((2R) -2 - {[ (2R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethyl] -amino} -propyl) -phenyl] -N- (3-chloro-5-hydroxybenzyl) -N-1-ethylacetamide, I 2 - [3 - ((2R) -2 - {[(2R) -2- (6-Arnopyridin-3-yl) -2-hydroxyethyl] amino} propyl) phenyl] -N- (3-chloro) 5-hydroxybenzyl) -acetamide, 2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino) -propyl) ) phenyl] -N- (4-hydroxy-3,5-dimethylbenzyl) acetamide, 2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl)] -2-hydroxy-ethyl] amino-propyl) pheny 1] -N- (3,5-dichloro-2-hydroxy-benzyl) acetamide, 3- (2- {[{2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] ] -1-amino} -2-methyl-propyl) -N- [2- (4-hydroxyphenyl) ethyl] -benzamide, 1- (2 - {[(2R) -2- (6-Aminopyridin-3-yl)] ) -2-hydroxyethyl] -amino) -2-methyl-propyl) -N- (4-hydroxybenzyl) benzamide, 3- (2 - {[(2R) -2- (6-Aminopyridin-3-yl)) -2-hydroxyethyl] -1 amino} -2-methyl-propyl) -N- (2-hydroxybenzyl) benzamide, 1- 3- (2- {[(2R) -2- (6-Aminopyridin-3-yl) -) 2-hydroxyethyl] -1 amino} -2-methyl-propyl) -N- [2- (3-hydroxyphenyl) ethyl] benzamide, 3- (2 - {[(2R) -2- (6-Aminopyridin)] -3-yl) -2-hydroxyethyl] -1-amino} -2-methyl-propyl) -N- [2- (4-hydroxy-3-methoxyphenyl) -1-ethyl] benzamide, 1026329 3- (2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl) -amino) -2-methyl-propyl) -N- (3-hydroxy-4-methylphenyl) -benzamide, 3- (2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -5 amino} -2-methyl-propyl) -N- [2- (4-hydroxy-3,5 -dimethoxy-phenyl) ethyl] benzamide, 3 - (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino) -2-methyl-propy 1) -N- (3-hydroxy-4-methoxyphenyl) -benzamide, 3 - (2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] amino) -2 - methyl propyl) - N - (3-hydroxyphenyl) benzamide, 3- (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino) -2-methyl- propyl) -N- (4-hydroxy-3-methoxybenzyl) -benzamide, 3- (2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl) -amino} -2 -methyl-propyl) -N- [5- (ethylsulfonyl) -2-hydroxy-phenyl] benzamide, 3 - (2 - {[(2R) -2- (6-7-minopyridin-3-yl) -2-) hydroxyethyl] -amino) -2-methyl-propyl) -N- (3-hydroxy-2-methylphenyl) -20 benzamide, 3- (2- {t (2R) -2- {6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino) -2-methyl-propyl) -N- (5-chloro-2-hydroxybenzyl) -benzamide, 3 - (2 - {[(2R) -2- (6-Aminopyridin-3-) yl) -2-hydroxyethyl) -25 amino} -2-methyl-propyl) -N- (4-hydroxy-1,2-biphenyl-3-yl) benzamide, 3 - (2 - {[(2R) -2-) (6-Aminopyridin-3-yl) -2-hydroxyethyl) -amino) -2-methyl-propyl) -N- [2-hydroxy-2- (3-hydroxyphenyl) -ethyl] -N-methylbenzamide, 3- (2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl) -amino} -2-methyl-propyl) -N- (2-hydroxy) ybenzyl) -N-methylbenzamide, 3- (2- {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl) -amino) -2-methyl-propyl) -N- (3, 5-dichloro-2-hydroxybenzyl) -35 benzamide, 1026329-

36 I

3- (2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

amino} -2-methyl-propyl) -N- [2- (2-hydroxyphenyl) ethyl] -1

benzamide, I

3- (2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

5 amino} -2-methyl-propyl) -N- [2- (3-ethoxy-4-hydroxyphenyl) -1

ethyl] benzamide, I

3- {2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

amino} -2-methyl-propyl) -N- [2- (3-hydroxy-4-methoxy-phenyl) -1

ethyl] benzamide, I

2- [3- (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1)

amino) -2-methyl-propyl) -benzoyl] -1, 3,4,5-tetrahydro-1H-2-l

benzazepin-8-ol, I

3 - (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

amino} -2-methyl-propyl) -N - [(4'-hydroxy-3-methyl-1,1'-1

Biphenyl-4-yl) methyl] benzamide, I

3- (2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

amino) -2-methyl-propyl) -N - [(3'-hydroxy-1,1'-biphenyl-2-yl) -1

methyl] benzamide, I

3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

20 amino} propyl) -N- (5-chloro-2-hydroxybenzyl) benzamide, I

3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

aminopropyl) -N- [2-hydroxy-2- (3-hydroxyphenyl) ethyl] -N-1

methyl benzamide, I

3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

Aminopropyl) -N- (2-hydroxybenzyl) -4-N-methylbenzamide, I

3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl) -1

aminopropyl) -N- [2- (3-ethoxy-4-hydroxyphenyl) ethyl) -1

benzamide, I

3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

Amino-propyl) -N- [2- (3-hydroxy-4-methoxyphenyl) ethyl] -1

benzamide, I

2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy] -1

ethyl] -amino} propyl) benzoyl] -2,3,4,5-tetrahydro-1H-2-l

benzazepin-8-ol, I

3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

aminopropyl) -N-ethyl-N- [2- (4-hydroxyphenyl) ethyl] benzyl

amide, I

1026329-I

37 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino-propyl) -N- (2-chloro-4-hydroxy-benzyl) - N-ethylbenzamide, 3- ((2R) -2- {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -5-aminopropyl) -N- (5-hydroxy-1) , 2,3,4-tetrahydronaphthalen-1-yl) benzamide, 2 - {4 - [3 - ((2R) -2- {[(2R) -2- (6-Aminopyridin-3-yl) - 2-hydroxyethyl] -amino} propyl) benzoyl] piperazin-1-yl} phenol, 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] - 10 amino] propyl) - N - (4-hydroxyphenyl) benzamide, 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino-propyl) -N- [4- (4-hydroxyphenyl) butyl] benzamide, 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino-propyl) - N - [(4'-hydroxy-1,1'-biphenyl-4-yl) benzamide, 3 - ((2 R) -2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2 - hydroxyethyl] - amino} propyl) - N - {[4 '- (hydroxymethyl) -1,1'-biphenyl-3-yl) methyl] benzamide, 3 - ((2R) -2 - {[(2R)) -2- (6-Amino-pyridin-3-yl) -2-hydroxyethyl] -amino} -propyl) -N- (2,4-dichloro-6-hydroxybenzyl) benzamide, 3- ((2R) -2- {[ (2R) -2- (6-Amin opyridin-3-yl) -2-hydroxyethyl] -amino} propyl) -N - [(3-fluoro-4'-hydroxy-1,1'-biphenyl-4-yl) methyl] benzamide, 3 - (( 2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino-propyl) -N - [(4'-hydroxy-3-methyl-1,1'-biphenyl) -4-yl) -25 methyl] benzamide, 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino} propyl) -N- (2-chloro-5-hydroxy-benzyl) -N-ethyl-benzamide, 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] - Amino-propyl) -N- [[2 '-hydroxy-1,1'-biphenyl-2-yl) methyl] -benzamide, 3 - ((2R) -2 - {[(2R) -2- (6- Aminopyridin-3-yl) -2-hydroxyethyl] -amino-propyl) -N - [(4'-hydroxy-1,1'-biphenyl-2-yl) methyl] -benzamide, 3 - ((2R) -2- {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino-propyl) -N- [3-hydroxy-5- (trifluoromethyl) benzyl] -N-methylbenzamide, 1026329-

I 38 I

I 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

Amino-propyl) -N- (3-chloro-5-hydroxy-benzyl) -N-ethylbenz-I

I amide, I

I 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

5 aminopropyl) -N- (3-chloro-5-hydroxybenzyl) benzamide, I

I 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

Amino-propyl) -N - [(4'-hydroxy-1,1'-biphenyl-3-yl) methyl] -1

I benzamide, I

I 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

I-amino-propyl) -N- (4-hydroxy-3,5-dimeth-yl-benzyl) -benzamide, I

I 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

Amino-propyl) -N- (3,5-dichloro-2-hydroxybenzyl) benzamide, I

I 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

Amino-propyl) -N- [2- (2-hydroxyphenyl) -ethyl] benzamide, I

3 - ((2R) -2 - {[(2R) -2- {6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

Amino-propyl) -N- (3-hydroxy-4-methoxyphenyl) benzamide, I

I 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

Amino-propyl) -N- (3-hydroxyphenyl) benzamide, I

I 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

Amino-propyl) -N- (4-hydroxy-3-methoxy-benzyl) -benzamide, I

3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl) -1

Amino-propyl) -N- [5- (ethylsulfonyl) -2-hydroxyphenyl] benz-1

I amide, I

I 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

Amino-propyl) -N- (2-hydroxy-5-methylphenyl) benzamide, I

I 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

Amino-propyl) -N- (3-hydroxy-2-methylphenyl) benzamide, I

I 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

Amino-propyl) -N- [2- (4-hydroxyphenyl) ethyl] benzamide, I

3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

Amino-propyl) -N- (4-hydroxybenzyl) benzamide, I

I 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

Amino-propyl) -N- (2-hydroxybenzyl) benzamide, I

I 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1

35 amino) propyl) -N- (3-hydroxybenzyl) benzamide, and I

3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl) -1

1 aminopropyl) -N- [2- (3-hydroxyphenyl) ethyl] benzamide. I

I 1026329-I

39

In one aspect of the present invention, the compounds of formula (1) wherein the (CH 2) n "C (= 0) Q 1 group is in the meta position are generally preferred.

Pharmaceutically acceptable salts of the compounds of formula (1) include the acid addition and base salts thereof.

Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include the acetate, asparagate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, glu -cepate, gluconate, glucuronate, hexafluorophosphate, hi-benzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, ma-leaat, malonate , mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharate, stearate, succinate, , tartrate, tosylate and trifluoroacetate salts.

Suitable base salts are formed from benefits that form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, 25 meglumine, olamine, potassium, sodium, trometharaine and zinc salts. Hemi salts of acids and bases can also be formed, for example, hemisulfate and hemicalcium salts.

For an overview of suitable salts, see "Hand-30 book of Pharmaceutical Salts: Properties, Selection, and

Use "by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Pharmaceutically acceptable salts of compounds of formula (1) can be prepared by one or more of three methods: (i) by reacting the compound of formula (1) with the desired acid or base; (Ii) by removing an acid or base labile protecting group from a suitable precursor of the compound of formula (1) or by a suitable cyclic precursor, for example a lactone or lactam Opening the ring by means of the desired acid or the desired base; or I (iii) by converting one salt of the compound of formula (1) to another by reaction with a suitable acid or base or with the aid of a suitable ion exchange column.

All three reactions are generally carried out in solution. The resulting salt can precipitate and be collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization in the resulting salt can vary from fully ionized to virtually non-ionized.

The compounds according to the invention can exist in both unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term "hydrate" is used when said solvent is water.

Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes in which, unlike the aforementioned solvates, the drug and the host are present in stoichiometric or non-stoichiometric how many quantities. Also included are complexes of the drug I which contain two or more organic and / or inorganic ingredients which may be in stoichiometric amounts. The resulting complexes can be ionized, partially ionized or non-ionized. For an overview of such complexes see J Pharm Sci, 64 I (8), 1269-1288 by Haleblian (August 1975).

I 1026329-41

Hereinafter, all references to compounds of formula (1) include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

The compounds of the invention include compounds of formula (1) as hereinbefore defined, including all polymorphs and crystal forms thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as defined above and isotope-labeled compounds with formula 1).

As indicated, so-called "prodrugs" of the compounds of formula (1) are also within the scope of the invention. Therefore, certain derivatives of compounds of formula (1) which have little or no pharmacological activity itself, when administered in or on the body, can be converted into compounds of formula (1) with the desired activity, for example by hydrolytic cleavage. Such derivatives are referred to as "prodrugs". Further information on the use of prodrugs 20 can be found in "Pro-drugs as Novel Delivery Systems, volume 14, ACS Symposium Series (T. Higuchi and W. Stella) and" Bioreversible Carriers in Drug Design ", Perga-mon Press, 1987 (ed. EB Roche, American. Pharmaceutical Association).

Prodrugs according to the invention can be produced, for example, by replacing suitable functionalities present in the compounds of formula (1) with certain parts known to those skilled in the art as "pro-parts" as described for example in "Design of Prodrugs" by H. Bund-30 (Elsevier, 1985).

Some examples of prodrugs according to the invention include: (i) where the compound of formula (1) contains a carboxylic acid functionality (-COOH), a. ester thereof, for example a compound in which the hydrogen of the carboxylic acid functionality of the compound of formula (1) is replaced by (C 1 -C 6) alkyl; 1026329-

42 I

(ii) where the compound of formula (1) is an alcohol function

(-OH), an ether thereof, for example

image a compound wherein the hydrogen of the al

alcohol functionality of the compound of formula I

5 (1) is replaced by (C 1 -C 6) alkanoyloxymethyl; and · I

(iii) where the compound of formula (1) is a primary or I

secondary amino functionality (-NH2 or -NHR where I

R Φ H) contains an amide thereof, for example an I

compound wherein, as may be the case, one or I

10 both hydrogens of the amino functionality of I

the compound of formula (1) has been replaced by I

(C1 -C10) alkanoyl. I

Further examples of replacement groups according to I

previous examples and examples of other prodrug I

15 types can be found in the aforementioned reference

rates. I

In addition, certain compounds of formula 1) I

themselves act as prodrugs of other compounds with FORI

mule (1). I

Also included are within the scope of the invention

tabolites of compounds of formula (1), i.e. I

gene, compounds formed in vivo after administration of the I

medicine. Some examples of metabolites according to I

the invention include I

(I) where the compound of formula (1) is a methyl group I

contains a hydroxymethyl derivative thereof (-CH 3 - »I

-CH 2 OH); I

(ii) where the compound of formula (1) has an alkoxy group I

contains a hydroxy derivative thereof (-OR - ♦ -OH); I

(Iii) where the compound of formula (1) is a tertiary I

amino group, a secondary amino derivative therein

of (-NR 1 R 2 - -NHR 1 or -NHR 2); I

(iv) where the compound of formula (1) is a secondary I

amino group, a primary derivative thereof I

35 (-NHR1 - -NH2); I

(v) where the compound of formula (1) is a phenyl moiety I

'contains a phenol derivative thereof (-Ph -PhOH); and I

1026329-I

43 (vi) where the compound of formula (1) contains an amide group, a carboxylic acid derivative thereof (-CONH 2 - ♦ CO-OH).

Compounds of formula (1) containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. Where a compound of formula (1) contains an alkenyl or alkenylene group, geometric cis / trans (or Z / E) isomers are possible. Where structural isomers are mutually convertible via a low energy barrier, tautomeric isomerism ("tautomerism") can occur. This may take the form of protonutemium in compounds of formula (1) which contain, for example, an imino, keto or oxime group, or so-called valentietautomerism in compounds containing an aromatic moiety. It follows that a single compound can exhibit more than one type of isomerism.

Included within the scope of the present invention are all stereoisomers, geometric isomers, and tautomeric forms of the compounds of formula (1), including compounds that exhibit more than one type of isomer, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counter ion is optically active, e.g., d-lactate or 1-lysine, or racemically, e.g., dl tartrate. or dl arginine.

Cis / trans isomers can be separated with. conventional techniques well known to those skilled in the art, for example chromatography and fractional crystallization.

Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example an alcohol, or, in the case where the compound of formula (1) an acid or basic moiety an acid or base such as tartaric acid I or 1-phenylethylamine. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization and one or both of the

diastereoisomers converted to the corresponding pure I

enantiomer (the corresponding pure enantiomers) with I

Means well known to those skilled in the art. I

Chiral compounds according to the invention (and chira-I

10 precursors thereof) can be obtained in enantio-I

I more-enriched form by chromatography, in the I

generally HPLC, over an asymmetric resin with a mobile I

I phase consisting of a hydrocarbon, generally hep

titanium or hexane, with 0 to 5 volume% isopropanol, in the I

I generally 2% to 20%, and 0 to 5 volume% of an alkyl

Amine, generally 0.1% diethylamine. Concentration I

I of the eluate yields the enriched mixture. I

I Stereo isomeric conglomerates can be separated I

Conventional techniques known to those skilled in the art I

See, for example, "Stereochemistry of Organic Com I

I pounds "by E. L. Eliel (Wiley, New York, 1994). I

According to one aspect of the present invention

I has the (R, R) stereoisomer of the formula below

Ile, where n and Q1 as defined above, in the I

25 is generally preferred: I

I? H H · 9 I ij I Ij-wA1 I 1026329-

The present invention encompasses all pharmaceutically acceptable isotope-labeled compounds of formula I (1) wherein one or more atoms have been replaced with atoms having the same atomic number, but an atomic mass or mass different from the atomic mass or mass number contained in the nature is considering.

Examples of isotopes suitable for incorporation into the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as UC, 13 C and 14 C, chlorine, such as 36 Cl, fluorine, such as ie F, iodine, such as 123 I and 125 I, nitrogen , such as 13N and. 1SN, oxygen, such as 150, NO and 180, phosphorus, such as 32 P, and sulfur, such as 35 S.

Certain isotope-labeled compounds of formula 10 (1), for example, those that incorporate a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e., 3 H, and carbon-14, i.e., 14 C, are particularly useful for this purpose in view of their ease of incorporation and easy means of detection thereof.

Substitution with heavier isotopes such as deuterium, e.g. 2H, may provide certain therapeutic benefits resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosing requirements, and may therefore be preferred under some circumstances.

Substitution with positron-emitting isotopes, such as nC, 18F, 150, and 13N, may be useful in Positron Emission Topography (PET) studies for investigating substrate receptor occupancy.

Isotope-labeled compounds. of formula (1) can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying Examples and Preparations using a suitable isotope-labeled reagent instead of the previously used unlabeled reagent.

Pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent may be isotope substituted, e.g. D2O, d6-acetone, d6-DMS0.

1026329-

I 46 I

The compounds of formula (1), the pharmaceutical I

Acceptable salts and / or derived forms thereof are I

Valuable pharmaceutically active compounds which I

I are suitable for the therapy and prophylaxis of numerous I

Disorders in which the P2 receptor is involved or where

I can induce benefit of agonism of this receptor, in I

I particularly the allergic and non-allergic airways I

I diseases but also in the treatment of other diseases such as I

I as, but not limited to, those of the nervous system, pre-I

I 10 mature labor pains, congestive heart failure, depression, inflammatory I

I and allergic skin diseases, psoriasis, proliferative

Iive skin diseases, glaucoma and in diseases where I

I is an advantage in reducing stomach acidity, in the I

I particularly with gastric and peptic ulceration. I

Compounds according to the invention intended for formula I

I maceutical use can be administered as crystalline

I line or amorphous products. These can for example be I

I obtained as solid plugs, powders or films using I

I of methods such as precipitation, crystallization, freezing

Drying, spray drying or evaporative drying, microwave or I

I radio frequency drying can be used for this purpose. I

I These can be administered alone or in combination I

With one or more other compounds of the invention

I or in combination with one or more other medicines (or I

As any combination thereof). In general, these I

I are administered as a formulation together with one or I

More pharmaceutically acceptable excipients. The term "ex-I

Ingredient "is used herein to mean any ingredient

I write differently from the connection (s) according to the invention

I thing. The choice of excipient will largely depend on I

I of factors such as the particular method of administration, the I

I effect of the excipient on solubility and stability, I

I and the nature of the dosage form. I

Pharmaceutical preparations suitable for delivery

I of compounds of the present invention and I

Methods for their preparation will be readily available to those skilled in the art

I become clear. Such compositions and I

Methods for their preparation can be found, for example, in "Remington's Pharmaceutical Sciences" 19th edition (Mack Publishing Company, 1995).

The compounds of the invention may be administered orally, oral administration may include ingestion such that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be used wherein the compound enters the blood stream directly from the mouth.

Formulations suitable for oral administration include solid formulations such as tablets, particles containing particulate substances, liquids, or powders, lozenges (including liquid-filled), chewing gums, multi- and nano-particulate substances, gels, solid solution , liposome, films, ovules, sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as fillers in soft or hard capsules and generally include a carrier, for example water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose or a suitable oil, and one or more emulsifiers and / or suspending agents. Liquid formulations can also be prepared by reconstituting a solid, for example from a sachet.

The compounds of the invention can be used in rapidly dissolving, rapidly disintegrating dosage forms, such as those described in Export Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001).

For tablet dosage forms, depending on dosage, the drug may make up 1 wt% to 80 wt% of the dosage form, more generally 5 wt% to 60 wt% of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrating agents include sodium starch flour glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose starch starch gelatinized starch starch gelatinized starch sodium alginate. In general, the disintegrant will comprise 1 wt% to 25 wt%, preferably 5 wt% to 20 wt% of the dosage form.

Binders are generally used to impart cohesive qualities to a tablet formulation.

Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural, and synthetic gums * polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrosis, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally include surfactants, such as sodium lauryl sulfate and polysorbate 80, and lubricants such as silica and talc.

If present, surfactants may comprise from 0.2% by weight to 5% by weight of the tablet, and lubricants may comprise from 0.2% by weight to 1% by weight of the tablet.

Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants generally comprise from 0.25% to 10% by weight, preferably from 0.5% to 3% by weight of the tablet.

Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives and flavor masking agents.

Illustrative tablets contain up to about 80% by weight of drug, about 10% by weight to about 90% by weight of binder, about 0% by weight to about 85% by weight of diluent, about 2% by weight up to about 10 wt% disintegrant, and about 0.25 wt% to about 10 wt% lubricant.

Tablet mixtures can be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet, dry or melt-granulated, melt-solidified, or extruded prior to tableting. The final formulation may comprise one or more layers and may be coated or uncoated, it may even be encapsulated.

The formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, band 1, by H. Lieber-man and L. Lachman (Marcel Dekker, New York, 1980),

Consumable oral films for human or veterinary use are generally flexible water-soluble or water-swellable thin film dosage forms which can be fast dissolving or mucous membrane adherent and generally a compound of formula (1), a film-forming polymer, a binder, a solvent, a humectant, a plasticizer, a stabilizer or emulsifier, a viscosity modifier and a solvent. Some components of the formulation may perform more than one function.

The compound of formula (1) can be water-soluble or insoluble. A water-soluble compound generally comprises 1 wt% to 80 wt%, more generally 20 wt% to 50 wt%, of the solutes. Less soluble compounds may comprise a larger proportion of the composition, generally up to 88% by weight of the dissolved substances. Alternatively, the compound of formula (1) may be in the form of multiparticulate beads.

The film-forming polymer can be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is generally present in the range of 0.01 to 99% by weight, more generally in the range of 30 to 80% by weight %.

Other possible ingredients include antioxidants, colorants, flavoring agents and flavor enhancers, preservatives, saliva stimulants, coolants, co-solvents (including oils), emollients, bulk agents, antifoaming agents, surface Active substances and taste masking agents.

Films according to the invention are generally prepared by evaporative drying of thin aqueous films covered on a peelable backing or paper. This can be done in a drying oven or tunnel, generally a combined coat dryer, or by freeze drying or vacuuming.

Solid formulations for oral administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed, maintained, pulsed, controlled, targeted, and programmed release.

Suitable modified release formulations for the purposes of the invention are described in U.S. Patent No. 6,106,864. Details of other suitable delivery technologies such as high energy dispersions I and osmotic and coated particles can be found in Pharmaceutical Technology On-line, 25 (2), 1-14, by

Verma et al. (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.

The compounds of the invention may also be administered directly in the blood stream, in muscle, or in an internal organ. Suitable means for parenteral administration include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intra-

Urethral, intrasternal, intracranial, intramuscular I

I and subcutaneous. Suitable devices for parenteral administration include needle (including micro needle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are generally aqueous solutions that may contain excipients such as salts, carbohydrates and buffering agents (preferably up to pH 3 to 9), but for some applications these may be formulated more appropriately as a sterile non-aqueous solution or as a dried form to be used together with a suitable carrier such as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, for example by lyophilization, can be easily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of formula (1) used in the preparation of parenteral solutions can be increased by the use of suitable formulation techniques, such as the incorporation of solubility enhancing agents.

Formulations for parenteral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, maintained, pulsed, controlled, targeted, and programmed release. Thus, compounds of the invention can be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot that provides modified release of the active compound. Examples of such formulations include drug-coated stents and poly (dl-milk coglycol) acid (PGLA) microspheres.

The compounds of the invention can also be topically administered to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dust powders, dressings, foams, films, skin patches, waffles, implants, sponges, fibers, bandages, and microemulsions. Liposomes can also be used. Typical carriers including alcohol, water, mineral oil, liquid petroleum jelly, white petroleum jelly, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers can be included - see, for example, J. Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (Oct. 1999).

Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and micro needle or needle free (e.g., Powder ject * 1, Bioject *, etc.) injection.

Formulations for topical administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, maintained, pulsed, controlled, targeted, and programmed release.

The compounds of the invention may also be administered intasasally or by inhalation, generally in the form of a dry powder (either alone, as a mixture, for example in a dry mixture with lactose or as a mixed component particle, e.g. mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohypertension). I drodynamics to produce a fine mist), or atomizer with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3, 3,3-heptafluoropropane. For intranasal use, the powder I may comprise a bioadhesive agent, for example chitosan or cyclodextrin.

The pressurized container, pump, spray, atomizer or nebulizer contains a solution or suspension of the compound (s) according to the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative means for dispersing, solubilizing, or extending, release of the active agent, a propellant (s) as a solvent, and an optional surfactant, such as sorbitan trioleate, oleic acid I, or an oligamic acid.

I 1028329-53

Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (generally less than 5 microns). This can be achieved by any suitable reduction method, such as spiral jet milling, fluid bed milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

Capsules (for example made from gelatin or hydroxypropyl methylcellulose), blisters and cartridges for use in an inhaler or insufflator can be formulated around a powder mixture of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as 1-leucine , mannitol, or magnesium stearate. The lactose can be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solvent formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain 1 pg to 20 mg of the compound of the invention per activation and the activation volume may vary from 1 µl to 100 µl. A typical formulation may include a compound of formula (1), propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

Suitable flavoring agents, such as menthol and levomethol, or sweetening agents, such as saccharin or saccharinarium, can be added to those formulations of the invention intended for inhaled / intranasal administration.

Formulations for inhaled / intranasal administration may be formulated to be immediate and / or modified release using, for example, 1026329-PGI. Modified release formulations include delayed, maintained, pulsed, controlled, targeted, and programmed release.

In the case of dry powder inhalers and aerosols 5, the dosage unit is determined by means of a

shutter that delivers a measured amount. Units I

according to the invention, I are generally ranked to administer a metered dose or "puff" containing 0.001 mg I to 10 mg of the compound of formula (1). The total daily dose will generally be in the range of 0.001 mg to 40 mg which can be administered in a single dose or, more commonly, as divided doses throughout the day.

The compounds of formula (1) are particularly suitable for administration by inhalation.

The compounds of the invention can be administered rectally or vaginally, for example in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives can be used as appropriate.

Formulations for rectal / vaginal administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed, maintained, pulsed, controlled, H-directed and programmed release.

The compounds of the invention can be administered directly to the eye or ear, generally in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline solution. Other formulations suitable for eye and ear administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone)

Ilicone) implants, waffles, lenses and particulate or J

I bladder systems, such as niosomes or liposomes. A polymer such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example hydroxypropyl methylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example as appropriate, may be incorporated together with a preservative such as benzalkonium chloride . Such formulations can also be delivered by iontophoresis.

. Formulations for eye / ear administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, or programmed release.

The compounds according to the invention can be combined with soluble macromolecular units, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, for solubility, dissolution rate, taste masking, bioavailability and / or stability for use in any of the aforementioned ways to improve administration.

For example, drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, the cyclodextrin can be used as an auxiliary additive, i.e. as a carrier, diluent or solubilizing agent. The most commonly used for these purposes are alpha, beta and gamma cyclodextrins, examples of which can be found in international patent applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.

To the extent that it may be desirable to administer a combination of active compounds, for example for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, of which at least one containing a compound according to the invention can suitably be combined in the form of a package suitable for co-administration of the compositions.

Therefore, the package according to the invention comprises two I or more separate pharmaceutical preparations, at least one of which contains a compound of formula (1) according to the invention, and means for separately maintaining said compound. preparations, such as a container, divided bottle, or divided foil package. An example of such a package is the familiar blister pack used for packaging tablets, capsules and the like.

The package according to the invention is particularly suitable for administering different dosage forms, for example parenterally, for administering the individual preparations with different dosage intervals, or for titrating the individual preparations. 15 rats against each other. To aid compliance, the package generally includes directions for administration and may be provided with a so-called memory aid.

For administration to human patients, the total daily dose of the compounds of the invention is generally in the range of 0.001 mg to 5000 mg, naturally dependent on the mode of administration.

For example, an intravenous daily dose can only be I

0.001 mg to 40 mg. The total daily dose I

I can be administered in single or divided doses. I

And, in the physician's opinion, outside of the I herein

I given typical trajectory. I

I These doses are based on an average human

Patient with a weight of approximately 65 kg to 70 I

1 kg. The physician will easily be able to determine doses I

I 30 for patients whose weight is outside this range I

I falls like children and the elderly. I

I For the avoidance of doubt include references

herein to "treatment", references to curative, I

I soothing and prophylactic treatment. I

According to another embodiment of the present I

In the invention, the compounds of the formula (1), or I

I pharmaceutically acceptable salts, derived forms or combination

And their compositions, can also be used as a combination with one or more additional therapeutic agents to be co-administered to a patient to achieve any particular desired therapeutic end result such as the treatment of pathophysiologically relevant disease processes including, but not limited to (i) air-tube narrowing, (ii) inflammation, (iii) allergy, (iv) tissue destruction, (v) signs and symptoms such as shortness of breath, cough. The second and more additional therapeutic agents may also be a compound of the formula (1), or a pharmaceutically acceptable salt, derived forms or compositions thereof, or one or more β2 agonists known in the art. More generally, the second and more therapeutic agents will be selected from a different category of therapeutic agents.

As used herein, the terms "co-administration", "co-administered" and "in combination with" concerning the compounds of formula (1) and one or more other therapeutic agents are intended to mean, and refer to includes the following: simultaneous administration of such a combination of compound (s) of formula (1) and therapeutic agent (s) to a patient in need of treatment, when such components are formulated together in a single dosage form which components at substantially the same time to said patient, • substantially simultaneous administration of such a combination of compound (s) of formula (1) and therapeutic agent (s) to a patient in need of treatment, such as constituents are formulated separately from each other in separate dosage forms which are taken by said patients at substantially the same time t, on which said constituents are delivered at the same time as said patient, consecutive administration of such a combination of compound (s) of formula (1) and therapeutic agent (therapeutic agent) means) to a patient in need of treatment, if such components are formulated separately from each other in separate dosage forms taken at successive times by said patient with a considerable interval of time between each administration to which said components are delivered to said patient at substantially different times; and consecutive administration of such a combination of compound (s) of formula (1) and therapeutic agent (s) to a patient in need of treatment if such components are formulated together in a single dosage form I which delivers said components in a controlled manner at which they are administered simultaneously, successively, and / or overlappingly at the same and / or different times by said patient, each part being capable of being administered by either the same or a different route.

Suitable examples of other therapeutic agents which may be used in combination with the compound (s) of formula (1), or pharmaceutically acceptable salts, derived forms or preparations thereof, include, but are in no way limited to: (a) 5-lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists, (b) leukotriene antagonists (LTRAs) including antagonists of LTB4, LTC4 , LTD4, and LTE4, I (c) Histamine receptor antagonists including H1 and H3 I antagonists, I (d) αχ and α2 adrenoceptor agonist vasoconstrictor sympathomimetic agents for decongestive application, I (e) Muscarinic M3 receptor antagonists or anticho I linergic agents, I (f) PDE inhibitors, e.g. PDE3, PDE4 and PDE5 inhibitors, I 1026329-59 (g) Theophylline, (h) Sodium cromoglycate, (i) COX inhibitors both non-selective and selective COX-1 or COX-2 inhibitors (NSAIDs) 5 (j) Oral and inhaled glucocorticosteroids, (k) Monoclonal antibodies active against endogenous inflammatory units, (1) Anti-tumor necrosis factor (anti-TNF-α) agents, (m) Adhesive molecule inhibitors including VLA-4 antagonist 10, (n) Kinine B2ι and B2 receptor antagonists, (o) Immunosuppressants, (p) Inhibitors of matrix metalloproteases (MMPs), (q) Tachykinin NK 1, NK 2 and NK 3 receptor antagonists, (r) Elastase inhibitors, (s) Adenosine A2a receptor agonists, (t) Inhibitors of urókinasé, (u) Compounds acting on dopamine receptors, eg D2 agonists, (v) Modulators of the NFicp path, e.g. IKK inhibitors, (w) Modulators of cytokine signaling pathways such as p38 MAP kinase or syk kinase, (x) Agents that can be classified as mucolytics or anti-cough agent, and (y) Antibiotics.

According to the present invention, combinations of the compounds of formula (1) with: - H3 antagonists, - muscarinic M3 receptor antagonists, - PDE4 inhibitors, - glucocorticosteroids, - adenosine A 2a receptor agonists, - modulators of cytokine signaling breath such as p38 MAP kinase or syk kinase, or leukotriene antagonists (LTRAs) including antagonists of LTB *, LTC4, LTD4 and LTÉ4, are further preferred.

According to the present invention, combinations of the compounds of formula (1) with: I - glucocorticosteroids, in particular inhaled I glucocorticosteroids with reduced systemic side effects, including prednisone, prednisolone, flunisolide, triamcinolone acetonide , beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide and mesasone furoate, or muscarinic M3 antagonists or anticholinergic agents including in particular ipratropium salts, namely bromide, tiotropium salts, namely bromide salts, oxit perenzepine, and telephenepine, further preferred.

It is to be understood that all references herein to treatment include curative, palliative and prophylactic treatment. The description which follows relates to the therapeutic applications for which the compounds of formula (1) can be made.

The compounds of formula (1) have the ability to interact with the p2 receptor and therefore have a wide range of therapeutic applications, as further described below, due to the essential role that the P2 receptor plays in the physiology of all mammals.

H

Therefore, a further aspect of the present invention relates to the compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, for use in the treatment of diseases, conditions and ailments wherein the P2 receptor is I involved. More specifically, the present invention also relates to the compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, for use in the treatment of diseases, conditions, and ailments selected from the group consisting of: Asthma of any type, aetiology, or pathogenesis, in particular asthma that is a member selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiological disturbances, extrinsic asthma caused by environmental factors, essential asthma with unknown or unclear cause, non-atopic asthma, bronchial asthma, emphysematous asthma, exercise induced asthma, allergen-induced asthma, cold air-induced. asthma, occupational asthma, inflammatory asthma caused by bacterial, fungal, protozoa, or viral infection, non-allergic asthma, incipient asthma, panting child syndrome and bronchiolytis, • chronic or acute trachea, chronic bronchitis, small airway obstruction, and emphysema • obstructive or inflammatory airway diseases of any type, etiology or pathogenesis, in particular an obstructive or inflammatory airway disease that is a member selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD which includes chronic bronchitis, pulmonary emphysema or dyspnea associated or unconnected with COPD, COPD characterized by irreversible, progressive airway obstruction, adult respiratory distress syndrome (ARDS), aggravation of respiratory hyperresponsiveness due to other drug therapy and respiratory disease associated with lung high blood pressure, 30 Bronchitis v of any type, aetiology or pathogenesis, in particular bronchitis which is a member selected from the group consisting of acute bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, produc bronchitis, staphylococcus or streptococcal bronchitis and vesicle bronchitis, acute lung injury, bronchiectase of any type, etiology or pathogenesis, in particular bronchiectase which is a member selected from the group consisting of cylindrical bronchial Chiectase, bladder-shaped bronchiectase, fusion-shaped bronchiectase, capillary bronchiectase, cystic bronchiectase, dry bronchiectase, and follicular bronchiectase.

A still further aspect of the present invention also relates to the use of the compounds of formula (1) or pharmaceutically acceptable salts, derived forms I or compositions thereof, for the preparation of a medicament with a p2 agonist activity. In particular I the present invention relates to the use of the compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, I for the preparation of a medicament for the treatment I of p2-mediated diseases and / or disorders, in particular the aforementioned diseases and / or disorders.

As a result, the present invention provides a particularly interesting method of treating a mammal, including a human being, with an effective amount of a compound of formula (1), I or a pharmaceutically acceptable salt, derived form or composition thereof. More precisely, the present invention provides a particularly interesting method for the treatment of P2-mediated diseases and / or disorders in a mammal, including a human being, in particular the diseases and / or disorders mentioned above. comprising administering to said mammalian I an effective amount of a compound of formula I (1), the pharmaceutically acceptable salts and / or derived forms thereof.

The following examples illustrate the preparation of the compounds of the formula (1): I 1026329.3 63

Example 1: 2- (3 - {(2 R) -2-Γ (2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethylamino] -propyl} -phenyl) -N-benzyl -acetamide 5 oh 2 H 2 N 2 IST CH 3 O 10

A solution of N-benzyl-2- {3 - ((2R) -2 - {(2R) -2- [6- (2,5-dimethyl-pyrrol-1-yl) -pyridin-3-yl] - 2-hydroxy-ethyl-amino} -propyl) -phenyl] -acetamide (preparation 1, 148 mg, 0.30 mmol) in ethanol (5 ml) was treated with hydroxylamine hydrochloride (103 mg, 1.48 mmol) and the resulting mixture became. heated to 85 ° C for 48 hours. The reaction was cooled to room temperature and passed through a strong cation exchange column eluting with methanol followed by 2 N ammonia in methanol to elute the product. Further purification by flash column chromatography eluting with dichloromethane: methanol: 880 ammonia (97: 3: 0.5 changing to 90: 10: 1 by volume) gave the title compound as a pale yellow solid (36 mg).

25 1 H NMR (400 MHz, CD3 OD): δ 7.78 (1H, s), 7.37 (1H, d), 7.27-7.00 (9H, m), 6.51 (1H, s) , 4.53 (1 H, s), 4.35 (2 H, s), 3.51 (2 H, s), 2.90-2.82 (2 H, m), 2.66-2.58 (3 H , m), 1.07 (3 H, d) ppm.

LRMS (APCI): m / z [M + H] + 419.

Example 2: 2- (3 - ((2R) -2 - [(2R) -2- (6-Amino-pyridin-3-yl) -1-2-hydroxy-ethylamino-3-propyl}) -phenyl) -N- (2-methoxy-benzyl) -acetamide I 5 9 ^ H π I h 2 n ^ nT CH 3 h 3 c "10 I Prepared from 2- [3 - ((2R) -2 - {( 2R) -2- [6- (2,5-dimethylpyrrol-1-yl) -pyridin-3-yl] -2-hydroxyethylamino} propyl) phenyl) -N- (2-methoxy) -benzyl) -acetamide (preparation 2) according to the method for example 1 and gives the title compound as a pale yellow foam.

1 H NMR (400 MHz, CD 3 OD): 5-7.77 (1 H, s), 7.36 (1 H, d), I 7.23-6.84 (8 H, m), 6.50 (1 H, d), 4.52 <1 H, m), 4.34 (2 H, 1 20 s), 3.78 (3 H, s), 3.50 (2 H, s), 2.88-2.81 (2 H , m), 2.66-1.57 (3H, m), 1.06 (3H, d) ppm.

I LRMS (APCI): m / z [M + H) + 449.

Example 3: 2- (3 - {(2 R) -2 - [(2 R) -2- (6-Amino-pyridin-3-yl) - 2-hydroxy-ethylamino] -propyl} -phenyl) - N- (2-ethoxy-benzyl) -acetamide I fh and I 30 I (II)

I / J, O / O

h2n n 3 v [I CH3 I 1026328-

35

I Prepared from 2- [3 - ((2R) -2 - {(2R) -2- [6- (2,5-dimethyl-pyrrol-1-yl) -pyridin-3-yl] -2 -hydroxy-ethylamino} -65-propyl-phenyl] -N- (2-ethoxy-benzyl) -acetamide (preparation 3) according to the method for Example 1 to give the title compound as a pale yellow foam.

1 H NMR (400 MHz, CD3 OD): δ - 7.78 (1 H, s), 7.37 (1 H, d), 5 7.21-7.00 (6 H, m), 6.90 (1 H, d) ), 6.83 (1 H, t), 6.50 (1 H, s), 4.52 (1 H, m), 4.35 (2 H, s), 3.99. (2H, m), 3.51 (2H, s), 2.89-2.81 (2H, m), 2.70-2.54 (3H, m), 1.34 (3H, d), 1.06 (3 H, d) ppm.

LRMS (APCI): m / z [M + H) + 463.

10

Example 4: 2- (3 - {(2 R) -2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethylamino-3-propyl} -phenyl) -N- (3 phenyl propyl acetamide

15 ° H H

JL CH, L L O

H2 N N 3 20

Prepared from 2- [3 - ((2R) -2 - {(2R) -2- (6- (2,5-dimethyl-pyrrol-1-yl) -pyridin-3-yl] -2-hydroxyethylamino) ) -propyl) -25 phenyl] -N- (3-phenyl-propyl) -acetamide (preparation 4) according to the method for Example 1 to give the title compound as a pale yellow foam.

* Η NMR (400 MHz, CD3 OD): δ = 7.79 (1 H, s), 7.38 (1 H, d), 7.24 (3 H, m), 7.24 (3 H, m), 7, 14 (5 H, m), 7.01 (1 H, d), 6.49 (1 H, d), 4.51 (1 H, m), 3.46 (2 H, s), 3.20 (2 H, t), 2.92-2.81 (2 H, m), 2.68-2.55 (5 H, m), 1.79 (2 H, m), 1.06 (3 H, d) ppm.

LRMS (APCI): m / z [M + H] + 447.

Example 5: 2- (3 - {(2 R) -2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -1-2-hydroxy-ethylamino] -propyl} - phenyl) -N-phenethyl-acetamide

I 5 OH

I J CH, O U

H 2 N N 3 ·.

1 ° I Prepared from 2- [3 - ((2R) -2 - {(2R) -2- [6- (2,5-dimethylpyrrol-1-yl) -pyridin-3-yl] -) 2-hydroxy-ethylamino} -propyl) -phenyl] -N-phenethyl-acetamide (preparation 5) according to the method for Example 1 to give the title compound I as a pale yellow foam.

1 X H NMR (400 MHz, CD 3 OD): δ - 7.79 (1 H, s), 7.38 (1 H, d), I 7.28-7.01 (9 H, m), 6.49 (1 H, d), 4.53 (1H, m), 3.42-3.37 (4H, m), 2.92-2.87 (2H, m), 2.77-2.73 (2H, m) ), 2.67-2.59 I20 (3H, m), 1.08 (3H, d) ppm.

I LRMS (APCI): m / z [M + H] + 433.

Example 6: 2- (3 - {(2R) -2 - [(2R) -2- (6-Amino-pyridin-3-yl) -1-2-hydroxy-ethylamino] -propyl} -phenyl) -N - (3,4-dimethyl-benzyl) -acetamide I, ^ ch3

I? H η h jTT

30 Jt. J CH. o h2n n 35 Prepared from N- (3,4-dimethyl-benzyl) -2- [3 - ((2R) -2- {(2R) -2- [6- (2,5-dimethylpyrrol-1) -yl) -pyridin-3-yl] -2-hydroxy-ethylamino} -propyl) -phenyl] -acetamide (preparation 1026329-67 6) according to the method for Example 1 to give the title compound as a pale yellow foam .

* Η NMR (400 MHz, CD3 OD): δ 7.77 (1 H, s), 7.35 (1 H, d), 7.19-6.96 (7 H, m), 6.50 (1 H, d), 4.50 (1 H, m), 4.27 (2 H, 5 s), 3.50 (2 H, s), 2.89-2.81 (2 H, m), 2.67-2.55 (3 H , m), 2.18 (6H, s), 1.06 (3H, d) ppm.

LRMS (APCI): m / z [M + H] + 419.

Example 7 2- (3 - {(2 R) -2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethylamino] -propyl) -phenyl) -N-indan-2 -yl acetamide

0 H K H

JL Λ CH, 11 J O ^ H 2 N N 1 2 3 4 5 6 7 8 9 10 11 1026329-2

Prepared from 2- [3 - ((2R) -2 - {(2R) -2- [6- (2,5-dimethyl-3-pyrrol-1-yl) -pyridin-3-yl] -2-hydroxy- ethylamino} propyl) 4 phenyl] -N-idan-2-yl-acetamide (preparation 7) according to the method for example 1 to give the title compound 6 as a pale yellow foam.

7 X H NMR (400 MHz, CD 3 OD): δ = 7.78 (1 H, s), 7.37 (1 H, d), 8 7.20-6.99 (8 H, m), 6.51 (1 H, S) ), 4.54 (2 H, m), 3.43 (2 H, 9 s), 3.23 (2 H, m), 2.89-2.79 (4 H, m), 2.69-2.56 (3 H, m), 10 1.07 (3 H, d) ppm.

11 LRMS (APCI): m / z [M + H] + 444.

68 - Example 8: 2- (3- {(2R) -2- [(2R) -2- (6-Amino-pyridin-3-yl) -2-hydroxyethylamino) -propyl} -phenyl) - N- (3,4-dichloro-benzyl) -acetamide I Γ H h / YCI: I JL & ch, IL ^ o h 2 n n * I 10 I Prepared from N- (3,4-dichloro-benzyl) -2 - [3 - ((2R) -2- {(2R) -2- [6- (2,5-dimethyl-pyrrol-1-yl) -pyridin-3-yl] -2-hydroxy-ethylamino) } -propyl) -phenyl] -acetamide (preparation I8) according to the method for example 1 to give the title compound as a pale yellow foam.

X H NMR (400 MHz, CD3 OD): δ = 7.78 (1 H, s), 7.41-7.35 (3 H, 1 m), 7.22-7.02 (5 H, m), 6.51 (1 H, s), 4.50 (1 H, m), 4.31 I 2 (2 H, s), 3.52 (2 H, s), 2.92-2.82 (2 H, m), 2, 70-2.56 (3 H, 1 m), 1.06 (3 H, d) ppm.

I LRMS (APCI): m / z [M + H] + 487/489.

Example 9: 2- (3 - {2 - [(2R) -2- (6-Amino-pyridin-3-yl) -2- hydroxyethylamino] -propyl} -phenyl) -N- (4 -hydroxy-3-methoxy-benzyl) -acetamide

H H H H ^ Y H

Prepared from 2- [3- (2 - {(2 R) -2- (6- (2,5-dimethyl-pyrrol-1-yl) -pyridin-3-yl) ] -2-hydroxy-ethylamino} -propyl) -phenyl] -N-1 1026329-69 (4-hydroxy-3-methoxy-benzyl) -acetamide (preparation 9) according to the process for Example 1 to give the title compound as a pale yellow foam.

1 H NMR (400 MHz, CD3 OD): S = 7.80 (1 H> m), 7.39 (1 H, m), 5 7.25-7.00 (4 H, m), 6.77 (1 H, bs) ), 6.69 (2 H, m), (1 H, m), 4.55 (1 H, m), 4.26 (2 H, s), 3.73 (3 H, s), 3.51 (2 h, d) , 2.90-2.58 (5H, m), 1.05 (3H, m) ppm.

LRMS (APCI): m / z [M + H] + 465, [M + Na] + 487, [M-H] +, 463.

Example 10: 2- (4- {2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethylamino] -2-methyl-propyl-phenyl) -N- ( 3-methoxy-benzyl) -acetamide 15 ° H h

j C X H 3 C CH 1 O

Η, Ν ^ ΙΤ J CH3 20

Prepared from 2- [4- (2 - {(2 R) -2- [6- (2,5-dimethyl-pyrrol-1-yl) -pyridin-3-yl] -2-hydroxyethylamino} -2- methyl-propyl) -phenyl] -N- (3-methoxy-benzyl) -acetamide (preparation 10) according to the method of Example 1 to give the title compound as a pale yellow foam.

X H NMR (400 MHz, CD3 OD): δ = 7.87 (1 H, s), 7.47 (1 H, d), 7.20 (3 H, m), 7.11 (2 H, d), 6.77 (3 H, m), 6.55 (1 H, d), 4.56 (1 H, m), 4.33 (2 H, s), 3.71 (3 H, s), 3.52 (2 H, s), 30 2.86 (1 H, m), 2.70 (3 H, m), 1.06 (3 H, s), 1.05 (3 H, s) ppm.

LRMS (APCI): m / z [M + H] + 463.

Example 11: 2- (4- {2 - [(2R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethylamino] -2-methyl-propyl} - phenyl) -N- (2,6-dimethoxy-benzyl) -acetamide-1 TH, CH 3 YY 4 x Ti j

JLJ H3C ch3 ^ n / ^ vS

I H 2 N 2 n H 2 I H 3 C-CT 1 Prepared from N- (2,6-dimethoxy-benzyl) -2- [4- (2- I {(2R) -2- [6- (2.5 -dimethyl-pyrrol-1-yl) -pyridin-3-yl] -2-hydroxyethylamino] -2-methyl-propyl) -phenyl] -acetamide I (preparation 11) according to the method for Example 1 to to give the title compound as a pale yellow foam: I. X H NMR (400 MHz, CD3 OD): δ - 7.86 (1 H, s), 7.46 (1 H, d), I 7.28-7.08 (5 H, m), 6.60 (2 H, d) ), 6.54 (1 H, d), 4.56 (1 H, 1 20 m), 4.42 (2 H, s), 3.76 (6 H, s), 3.45 (2 H, s), 2 87 (1 H, 1 m), 2.70 (3 H, m), 1.06 (3 H, s), 1.05 (3 H, s) ppm.

I LRMS (APCI): m / z [M + H] + 493.

Example 12: 2- (3- {2- [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxyethylamino] -2-methyl-propyl} -phenyl) - N- (4-sulfamoylbenzyl) -acetamide

OH

Prepared from 2- [3- (2 - {(2 R) -2- [6- (2,5-dimethyl-pyrrol-1-yl) -pyridin-3-] yl] -2-hydroxy-ethylamino) -2-methyl-propyl) -1026329- (phenyl) -N- (4-sulfamoyl-benzyl) -acetamide (preparation 12) according to the process for Example 1 to obtain the title compound to give as a pale yellow foam.

1 H NMR (400 MHz or CD 3 OD): δ - 7.85 (1 H, s), 7.79 (2 H, d), 5.48 (1 H, d), 7.38 (2 H, d), 7, 25-7.10 (3 H, m), 7.05 (1 H, s), 6.58 (1 H, d), 4.58 (1 H, m), 4.40 (2 H, s), 3.55 (2 H, s), 2.82 (1 H, m), 2.75-2.60 (3 H, m), 1.05 (3 H, s), 1.04 (3 H, s) ppm.

LRMS (APCI): m / z [M + H] + 512.

10

Example 13: 2- (3- {2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethylamino] -2-methyl-propyl} -phenyl) -N- ( 2-ethoxy-benzyl) -acetamide 15 BJ HjC CH 3 O 4 -CH 3

H2 N

20

Prepared from 2- [3- (2 - {(2 R) -2- [6- (2,5-dimethyl-pyrrol-1-yl) -pyridin-3-yl] -2-hydroxyethylamino} -2- methyl-propyl) -25 phenyl] -N- (2-ethoxy-benzyl) -acetamide (preparation 13) according to the method for example 1 to give the title compound as a pale yellow foam.

1 R NMR (400 MHz, CD3 OD): δ = 7.87 (1 H, s), 7.48 (1 H, d), 7.21-7.04 (6 H, m), 6.87 (1 H, d) ), 6.83 (1 H, t), 6.57 (1 H, 30 d), 4.57 (1 H, m), 4.36 <2 H, s), 4.01 (2 H, q), 3, 52 (2 H, s), 2.88-2, 83 (1 H, m), 2.74-2.64 3 H, m), 1.32 (3 H, t), 1.03 (3 H, s), 1.02 (3 H, s) ppm.

LRMS (APCI): m / z [M + H] + 477.

Example 14: 2- (3 - {2 - [(2R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethylamino] -2-methyl-propyl} - phenyl) -N-indan-2-yl-acetamide

I H

I J L J H sc CH 0 O - (7 I h 2 n n I 10 I Prepared from 2- 3 - (2 - {(2 R) -2- [6- (2,5-dimethyl-pyrrol-1-yl) ) -pyridin-3-yl] -2-hydroxy-ethylamino} -2-methyl-propyl) -

Phenyl] -N-indan-2-yl-acetamide (preparation 14) according to I

I method for example 1 to give the title compound I as a pale yellow foam.

10 NMR (400 MHz, CD 3 OD): δ <= 7.90 (1H, s), 7.48 (1H, d), I 7.22-7.11 (7H, m), 7.04 (1H , d), 6.57 (1 H, d), 4.56 (2 H, 20 m), 3.45 (2 H, s), 3.24-3.20 (2 H, m), 2.86 -2.67 (6H, m), 1.07 (3H, s), 1.06 (3H, s) ppm.

I LRMS (APCI): m / z [M + H] + 459.

Example 15: 2- (3- {2- [(2 R) -2- (6-Amino-pyridin-3-yl) -2- I

Hydroxyethylamino] -2-methyl-propyl} -phenyl) -N-benzyl-1

acetamide I

J J J H3 C CH, J O

I h2n ^ n 3 3X ^ I 35

I Prepared from N-benzyl-2- [3- (2 - {(2 R) -2- [6- (2,5-dimethyl)]

Pyrrol-1-yl) -pyridin-3-yl] -2-hydroxy-ethylamino) -2-methyl-1

Propyl) -phenyl] -acetamide (preparation 15) according to the method for Example 1 to give the title compound as a colorless foam.

1 H NMR (400 MHz, CD3 OD): δ = 7.87 (1H, m), 7.48 (1H, dd), δ 7.28-7.13 (8H, m), 7.05 (1H, d), 6.57 (1 H, d), 4.59-4.56 (1 H, m), 4.36 (2 H, s), 3.54 (2 H, s), 2.90-2.85 (1 H, m), 2.77-2.67 (3 H, m), 1.08 (3 H, s), 1.05 (3 H, s) ppm.

LRMS (electrospray): m / z [M + H] + 433, [M + Na] + 455, (M-H) "431.

10

Example 16: 2- (3- (2 - [(2R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethylamino] -2-methyl-propyl} -phenyl) -N-phenethyl -acetamide 15

f H

Jf J h3 ° °

Η2ΝΓ N

20

Prepared from 2- [3- (2 - {(2 R) -2- [6- (2,5-dimethyl-pyrrol-1-yl) -pyridin-3-yl] -2-hydroxyethylamino) -2- methyl-propyl) -25. phenyl] -N-phenethyl-acetamide (preparation 16) according to the method for Example 1 to give the title compound as a colorless foam.

X H NMR (400 MHz, CD 3 OD): δ = 7.91-7.89 (1 H, m), 7.51-7.49 (1 H, m), 7.24-7.05 (9 H, m), 6.58 (1 H, d), 4.60-4.57 (1 H, 30 m), 3.44 (2 H, s), 3.42-3.38 (2 H, m), 2.90-2 , 85 (1H, m), 2.77-2.66 (6H, m), 1.08 (3H, s), 1.05 (3H, s) ppm.

LRMS (electrospray): m / z [M + H] + 447, [M + Na] + 469, [M-H] ~ 445.

1026329-

74

Example 17: 2- (3 - {2 - [(2R) -2- (6-Amino-pyridin-3-yl) -2- I

1-hydroxy-ethylamino] -2-methyl-propyl} -phenyl) -N- (3-phenyl-1)

Propyl) -acetamide I

I 5 I

I H H I J H J C CH 3 II J H I N 2 3 3

I 10 I

I Prepared from 2- [3- (2 - {(2 R) -2- [6- (2,5-dimethyl-pyrrol-1-)]

1-yl) -pyridin-3-yl] -2-hydroxy-ethylamino} -2-methyl-propyl) <-I

Phenyl] -N- (3-phenyl-propyl) -acetamide (preparation 17) vol

I according to the method for example 1 for the title compound I

I give as a colorless foam. I

1 X H NMR (400 MHz, CD 3 OD): δ = 7.88 (1 H, s), 7.49-7.47 (1 H, 1 m), 7.24-7.11 (8 H, m), 7, 06-7.04 (1 H, m), 6.56 (1 H, d), 4.58-4.55 (1 H, m), 3.47 (2 H, s), 3.18 (2 H, t), 2.88-2.83 I qh, m), 2.75-2.65 (3 H, m), 2.59-2.55 (2 H, m), 1.81-1.74 I (2 H, m), 1.06 (3 H, s), 1.03 (3 H, s) ppm.

LRMS (electrospray): m / z [M + H] + 461, [M + Na] + 483, [M-H] "I 459.

I 1026329-75

Example 18: 2- (3- {2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethylamino] -2-methyl-propyl} -phenyl) -N- ( 3/5-di-, chlorobenzyl) -acetamide 5 ClOH, HH, JH, CCH, H2O, TNO

Prepared from N- (3,5-dichloro-benzyl) -2- [3- (2 - {(2 R) -2- [6- (2,5-dimethyl-pyrrol-1-yl) -pyridin-3- yl] -2-hydroxy-ethylamino} -2-methyl-propyl) -phenyl] -acetamide (preparation 18) according to the method for Example 1 to give the title compound as a colorless foam.

X H NMR (400 MHz, CD3 OD): δ = 7.87 (1 H, s), 7.49-7.47 (1 H, m), 7.26-7.12 (7 H, m), 6.56 ( 1 H, d), 4.59-4.56 (1 H, m), 4.32 (2 H, s), 3.55 (2 H, s), 2.90-2.85 (2 H, m), 2.77-2.66 (2 H, m), 1.07 (3 H, s), 1.04 (3 H, s) ppm.

LRMS (electrospray): m / z [M + H] + 501/503, [M + Na] + 523/525, [M-H] "499/501.

1026328-

76 I

Example 19: 2- (3- {2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-]

hydroxyethylamino] -2-methyl-propyl} -phenyl) -N- (3,4-di-l

methylbenzyl) -acetamide I

5 I

0H Η [Ί I

1 J HSC CH, HJ O CH, I

10 ^ N I

Prepared from N- (3,4-dimethyl-benzyl) -2- [3- (2 - {(2R) -2- I

[6- (2,5-diroethyl-pyrrol-1-yl) -pyridin-3-yl] -2-hydroxy-1

Ethylamino} -2-methyl-propyl) -phenyl] acetone (preparation I

19) according to the method for example 1 to give the title reference

to give binding as a colorless foam. I

X H NMR (400 MHz, CD3 OD): δ = 7.87 (1 H, s), 7.49-7.47 (1 H, I

m), 7.22-7.13 (3H, m), 7.05-6.95 (4H, m), 6.56 (1H, d), I

20 4.58-4.55 (1 H, m), 4.36 (2 H, s), 3.51 (2 H, s), 2.89-2.84 I

(1 H, m), 2.75-2.65 (3 H, m), 2.26 (3 H, s), 2.14 (3 H, s), I

1.06 (3 H, s), 1.04 (3 H, s) ppm. I

LRMS (electrospray): m / z [M + H] + 461, [M + Na] + 483, [M-H] "I

459 I

25 I

1026329- 77

Example 20: 2- (3- (2 - [(2 R) -2- (6-Amino-pyridin-3-vi) -2-hydroxy-ethylamino] -2-methyl-propyl} -phenyl) -N- ( 3,4-dichlorobenzyl) -acetamide XX H3 C ChX ft H2 N N 3 3 3 10

Prepared from N- (3,5-dichloro-benzyl) -2- [3- (2 - {(2 R) -2- [6- (2,5-dimethyl-pyrrol-1-yl) -pyridin-3- yl] -2 ^ * hydroxy-ethylamino} -2-methyl-propyl) -phenyl] -acetamide (preparation 20) according to the method for Example 1 to give the title compound as a colorless foam. 1 H NMR (400 MHz, CD3 OD): δ = 7.88 (1 H, s), 7.49-7.47 (1 H, m), 7.39 (1 H, d), 7.33 (1 H, m) , 7.24-7.11 (4H, m), 7.07-20 7.05 (1H, m), 6.56 (1H, d), 4.59-4.57 (1H, m), 4.32 (2H, s), 3.54 (2H, s), 2.90-2.85 (1H, m), 2.76-2.66 (3H, m), 1.06 (3H, s), 1.04 (3 H, s) ppm.

LRMS (electrospray): m / z [M + H] + 501/503, [M + Na) + 523/525, [M-H]] 499/501.

25

Examples 21-27 (R as defined in table 1)

OH

ΓΓ ^ ΥΎΥΥ1 '35 1026329 “I 78

Prepared using the method for preparation 1 I

I using the acid from preparation 30 and the appropriate I

I amine to give amides which were subjected to the I

I conditions for Example 1 without purification. Pure I

HPLC ring: I

Column: Phenomenex Luna C18, 10 .mu.m, 150 x 10 mm

I capture temperature I

Eluent A: 0.05% diethylamine in water, Eluent B: acetoni

I vibrate I

Sample solvent: 90% dimethyl sulfoxide in water. I

I Gilson LC pump gradient timetable Gilson 119 UV detector / I

I collect 225 (nm) I

I Time A% B% Flow rate (ml / min) I

I 0.00 80.0 20.0 6.000 I

I 0.20 80.0 20.0 6.000 I

I 7.00 5.0 95.0 6.000 I

I 9.00 5.0 95.0 6.000 I

I 9.10 80.0 20.0 6.000 I

I 10.50 80.0 20.0 6.000 I

I Dual sensitivity 200 / peak sensitivity 60 / peak I

Width 0.3 min. I

I Gilson auto sample injection volume (μ1) - 550.00 I

I gave the title connections. I

I LRMS (electrical I

Pre-Retention I

IR spray) I

I display time (min) - I

I ______ [M + H] [M-H] * I

I 21 5.91 505 503 I

I F I

I P | 02 63 29 79 22 5.91 503 501

F

23 5.9 505 503 κΑΛΡ .____ o'CH ’24 4'76 509 507 UU ^ ch; 0λ; 25 5.95 503 501 26 5.84 505 503

F'T'F

F

F '27, 5.79, 505, 503

F ^ TT

_ [__ F__J _ [____ 1026329-

80 I

Example 28: 2- (3 - {(2 R) -2- [2- (6-Aminopyridin-3-yl) -2-]

hydroxyethylamino] -2-methylpropyl} phenyl) -N- (4f-hydroxybi)

phenyl-3-ylmethyl) acetamide I

5 I

IV

h2n ^ n ^ OH I

ίο. I

Prepared according to the method described for example I

1 using the amide from preparation 48 to give the title I

15 as a light brown solid. I

X H NMR (400 MHz, CD3 OD): δ = 7.86 (1 H, m), 7.45 (1 H, dd), I

7.27-7.40 (5H, m), 7.17-7.24 (2H, m), 7.11-7.13 (2H, m), I

7.03-7.05 (1H, m), 6.79-6.83 (2H, m), 6.54 (1H, d), 4.53 l

(1H, dd), 4.41 (2H, s), 3.54 (2H, s), 2.80 (1H, dd), 2.59-1

2.70 (3H, m), 1.01 (3H, s), 0.98 (3H, s) ppm. I

LRMS (electrospray): m / z [M + H] + 525, [M + Na] + 547. I

Example 29: 2- (3 - {(2 R) -2- [2- (6-Aminopyridin-3-yl) -2-]

hydroxyethylamino] -2-methylpropyl) phenyl) -N- (4'-hydroxy bis)

Phenyl-4-ylmethyl) acetamide I

OH I

Η., Ν '^ ΝΓ O I

Prepared according to the method described for example I

1 using the amide from preparation 49 to give the title I

to give compound like a pink foam. I

«026329- I

81 * H NMR (400 MHz, CD3 OD): δ = 7.87 (1H, d), 7.39-7.48 (5H, m), 7.14-7.26 (5H, m), 7, 05-7.07 (1H, m), 6.81-6.85 (2H, m), 6.55 (1H, d), 4.54 (1H, dd), 4.37 (2H, s) , 3.54 (2H, s), 2.83-2.88 (1H, m), 2.65-2.76 (3H, m), 1.05 (3H, s), 5.02 ( 3H, s) ppm.

LRMS (electrospray): m / z [M + H] + 525, [M + Na] + 547.

Example 30: 2- (3 - {(2 R) -2 - [(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethylamino] propyl} phenyl) -N- (4'-hydroxy-biphenyl) -3-10 ylmethyl) acetamide ° H Η H 1 2 3 4 5 6 1026329-

Prepared according to the method described for Example 2 using the amide from preparation 50 to give the title compound 3 as a colorless foam.

4 * H NMR (400 MHz, CD3 OD): δ = 7.76 (1 H, d), 7.27-7.41 (6 H, 5 m), 7.09-7.22 (4 H, m), 7 00-7.03 (1 H, m), 6.79-6.83 (2 H, 6 m), 6.47 (1 H, d), 4.48 (1 H, dd), 4.40 (2 H, s), 3.53 (2H, s), 2.79-2.88 (2H, m), 2.59 (2H, dd), 2.50-2.55 (1H, m), 1.00 (3 H, d) ppm.

LRMS (electrospray): m / z [M + H] + 511, [M + Na] + 533.

82

Example 31: 2- (3- ((2R) -2- [(2R) -2- (6-, Aminopyridin-3-yl) -1

2-hydroxyethylamino] propyl) phenyl) -N- (4-hydroxynaphthalen-1-)

Iylmethyl) acetamide I

I 5 I

I I

I 0 H Η H f | nT I

I 10 h2n ΤΧΓΤ

I Prepared according to the method described for Example I

I 1 using the amide from preparation 57 to give the title I

To give a compound as a light brown solid. I

1 H NMR (400 MHz, CD3 OD): δ = 8 / 17-8.20 (1 H, m), 7.81-7.83 I

I (1H, m), 7.71 (1H, d), 7.36-7.38 (2H, m), 7.7.28 (1H, dd), I

I 7.18 (1H, d), 7.09-7.13 (2H, m), 6.92-6.94 (2H, m), 6.68 I

I (1H, d), 6.43 (1H, d), 4.65 (2H, d), 4.44 (1H, dd), 3.43 I

I 20 (2H, s), 2.71-2.79 (2H, m), 2.53-2.58 (2H, m), 2.43-2.48 I

I (1 H, m), 0.95 (3 H, d) ppm. I

I LRMS (APCI): m / z [M + H] + 485, [M + Na] + 507. I

Example 32: 3- {2 - [(2R) -2- (6-Aminopyridin-3-yl) -2- I

Hydroxyethylamino] -2-methylpropyl} -N- (4 * -hydroxybiphenyl-3-)

1 ylmethyl) benzamide I

OH H 1

I 30

I h2n ^ n ^ I

I 1028329-

Prepared according to the method described for Example I

I 1 using the amide from preparation 52 to give the title I

I to give a compound as an off-white solid. I

83 1 H NMR (400 MHz, CD3 OD): δ - 7.86 (1 H, d), 7.71-7.75 (2 H, m), m 7.53 (1 H, bs), 7.33-7, 46 (7H, m), 7.25-7.27 (1H, d), 6.81-8.85 (2H, m), 6.49 (1H, d), 4.57 (1H, dd) , 4.56 (2H, dd), 2.87-2.95 (2H, m), 2.69-2.74 (2H, m), 1.11 (3H, s), 5.05 ( 3H, s) ppm.

LRMS (APCI): m / z [M + H] + 511, [M + Na] + 533.

Example 33: 3- {(2R) -2- [2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethylamino] -2-methyl-propyl} -N- [2- (4-hydroxy -10 phenyl) -2-methyl-propyl-3-benzamide

° H H 0 fY ° H

H2 N

Prepared according to the method described for Example 1 using the amide from preparation 53 to give the title compound as a light brown solid.

X H NMR (400 MHz, CD3 OD): δ = 7.87 (1 H, d), 7.53-7.55 (1 H, m), m 7.48-7.51 (2 H, m), 7.32 -7.33 (2H, m), 7.24 (2H, dd), 672 (2H, dd), 6.56 (1H, dd), 4.55 (1H, dd), 3.51 (2H , s), 2.80-2.92 (2H, m), 2.70-2.74 (2H, m), 1.33 (6H, s), 1.08 (3H, s), 1, 04 (3 H, s) ppm.

LRMS (APCI): m / z [M + H] + 477.

1026329-

84 I

Example 34- {3 - [(2R) -2- (6-Aminopyridin-3-yl) -2-]

hydroxyethylamino] -2-methylpropyl] -N- [2- (4-hydroxy-2,5-I

dimethylphenyl) ethyl] benzamide I

5 '

0H I

10 2 I

Prepared according to the method described for example I

1 using the amide from preparation 54 to give the title I

15 to give a compound as a colorless solid. I

X H NMR (400 MHz, CD3 OD): 8-7.89 (1H, d), 7.62-7.67 (2H, 1)

m), 7.83-7.89 2, m), 6.83 (1 H, s), 6.57 (1 H, d), 6.53 (1 H, I)

s), 4.57 (1H, dd), 3.44-3.48 (2H, m), 2.87-2.97 (2H, m), I

2.70-2.80 (4 H, m), 2.21 (3 H, s), 2.08 (3 H, s), 1.11 {3 H, I

20 s), 1.04 (3 H, s) ppm. I

LRMS (APCI): m / z [M + H] + 477, [M-H] "475. I

Example 35: 3- {2- [(2 R) -2- (6-Aminopyridin-3-yl) -2-]

hydroxyethylamino] -2-methylpropyl) -N- [2- (4-hydroxy-2,3-I

Dimethylphenyl) ethyl] benzamide I

/ ° h I

0H h 0 I

h2u ^ k I

Prepared according to the method described for example I

1 using the amide from preparation 55 to give the title I

compound as a colorless solid. I

1026329-I

85 * H NMR (400 MHz, CD3 OD): δ 1.05 (3 H, s), 1.12 (3 H, s), 21.12 (3 H, s), 2.23 (3 H, s), 270.275 (2H, m), 283-299 (4H, m), 2.45-2, 48 (2H, m), 4.68-4.51 (1H, m), 6.53-6.59 ( 2H, m), 6.80 (1H, d), 7.33-7.41 (2H, m), 7.51 (1H, dd), 7.62-5 7.67 (2H, m), 7.90 (1 H, d) ppm.

LRMS (electrospray): m / z [M + H] + 477, [M + Na] + 499.

Example 36: 3 - {2 - [(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethylamino] -2-methylpropyl} -N- [2- (4-hydroxy-2-10 methylphenyl) ethyl ] benzamide oh π o ^ 1 2 3 4 5 6 1026329-

Prepared according to the method described for Example 2 using the amide from preparation 56 to give the title compound as a beige-colored foam.

4 * H NMR (400 MHz, CD3 OD): δ = 1.06 (3 H, s), 1.13 (3 H, s), 5.14 (3 H, s), 2.72-2.79 (4 H , m), 2.87-2.98 (2H, m), 3.46-6.64 (2H., m), 4.69 (1H, dd), 6.57 (1H, d), 6.64 (1H, d), 6.85 (1H, dd), 6.93 (1H, d), 7.33-7.39 (2H, m), 7.60 (1H, dd), 7 , 61 (1H, bs), 7.63 (1H, dt), 7.89 (1H, d) ppm.

LRMS (APCI): m / z [M + H] + 463, [M-H] "461.

86 I

Example 37: 3 - {(2R) -2 - [(2R) -2- (6-Aminopyridin-3-yl) -2- I

hydroxyethylamino] propyl} -N- [2- (4-hydroxy-2,5-dimethyl-1)

phenyl) ethylbenzamide I

5 I

° h π O I

10 I

Prepared according to the method described for example I

1 using the amide from preparation 57 to give the title I

15 to give a compound as an off-white solid. I

* H NMR (400 MHz, CD3 OD): δ * 7.80 (1H, d), 7.60-7.62 (1H, I

m), 7.57-7.58 (1H, m), 7.39 (1H, dd), 7.29-7.36 (2H, m), I

6.55 (1 H, s), 6.50 (1 H, d), 4.54 (1 H, dd); 3.46-3.50 (2 H, 1

m), 2.96 (1H, q), 2.78-2.90 (4H, m), 2.61-2.72 (2H, m), I

2.24 (3 H, s), 2.09 (3 H, s), 1.07 (3 H, d) ppm. I

LRMS (APCI): m / z [M + H] + 463, [Μ-ΗΓ 461. I

Example 38: 3 - {(2 R) -2 - [(2 R) -2- (6-Aminopyridin-3-yl) -2- I

hydroxyethylamino] propyl} -N- [2- (4-hydroxy-2,3-dimethyl-1

Phenyl) ethyl 3 benzamide I

0H I

h2n ^ n ^ I

Prepared according to the method described for example I

1 using the amide from preparation 58 to give the title I

to give a connection as a pale pink foam. I

1026329-I

87 * H NMR (400 MHz, CD3 OD): 6 - 1.08 (3 H, d), 2.13 (3 H, s), 2.26 (3 H, s), 2.61 (1 H, dd), 2 70 (1H, dd), 2.79-2.81 (4H, m), 2.98 (1H, q), 3.46-3.49 (2H, s), 4.55 (1H, dd) ), 6.50 (1 H, d), 6.54 (1 H, d), 6.81 (1 H, d), 7.29-7.86 (2 H, m), 5.89 (1 H, dd) ), 7.58 (1H, bs), 7.60 (1H, dt), 7.80 (1H, d) ppm.

LRMS (electrospray): m / z [M + H] + 463, [M + Na] + 485.

Example 39: 3 - {(2 R) -2 - [(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethylamino] propyl) -N- [2- (4-hydroxy-2-methylphenyl) ethyl] benzamide

OHO A / OH

20

Prepared according to the method described for Example 1 using the amide from preparation 59 to give the title compound as a beige-colored foam.

X H NMR (400 MHz, CD3 OD): δ = 1.08 (3 H, d), 2.15 (6 H, s), 2.62 (1 H, dd), 2.70-2.92 (5 H, m ), 2.98 (1H, q), 3.51 (2H, t), 4.55 (1H, dd), 6.50 (1H, d), 6.65 (1H, d), 6.86 (1H, dd), 6.95 (1H, d), 7.28-7.36 (2H, m), 7.39 (1H, dd), 7.56 (1H, bs), 7.59 ( 1 H, dt), 7.80 (1 H, d) ppm.

LRMS (APCI): m / z [M + H] + 449, [M-H] "447.

30

Examples 40 to 169 were prepared using the following procedure:

The acid (150 μΐ of a 0.2 M solution) in water-free dimethylacetamide / 3.75% triethylamine was added to each well of a 96-well polypropylene plate (2 ml volume per well). 225 μΐ 0.2 M solutions were added 1026329-88

gene of the amines in anhydrous dimethylacetamide / 3.75% I

triethylamine was added to each well, followed by 225 l

μΐ of a freshly prepared 0.25 M solution of 2- (1H-I

benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophos-I

Fate in dimethylacetamide was manually added to each well I

added. The plates were sealed with a Teflon sheet I.

and a rubber gasket and tightly sandwiched between two aluminum I

and are shaken for 3 days and heated to 60 ° C, ver I

then the plate was opened and evaporated. I

Methanol (200 μΐ) was added to each well and the I

plate closed again and shaken for 30 minutes until all I

remains were dissolved. The plates were reopened and I

hydroxylamine hydrochloride (200 μΐ) of a 1.0 M solution I

in anhydrous ethanol was added to each well I manually

15 added. The plate was sealed with a Teflon sheet and I

a rubber gasket and firmly clamped between two aluminum I

blocks and shaken for 16 hours and heated to 80 ° C, then I

evaporated to dryness. I

Dimethyl sulfoxide (300 μΐ) was added to each well

20 and the plate sealed and shaken for 30 minutes until all I

remains were dissolved. The shelf was opened, water (150 l

μΐ) was added manually and the plate sealed and I

manually shaken for 1 min. I

Preparative reverse phase chromatography was performed

Fed on a Phenomenex Luna C18, 10 µm HPLC column (150 L

x 10 mm i.d.) at room temperature. The column flow was 8 l

ml / min. The mobile phase used was a binary acetone

vibrate / water buffered with 0.05% (vol / vol) diethylamine. I

Initial chromatographic conditions were included

30 set to 0% acetonitrile. Sample separation was achieved I

by increasing the acetonitrile concentration to 70% by volume

11.60 minutes with a holding of an additional 0.5 l

minutes before reconditioning of the coffee

lom at 0% acetonitrile for a further 2.5 minutes. I

35 Fractions were collected with the aid of a UV trigger I

based on 225 nm and 254 nm wavelengths, the dual I

1026329-89 sensitivity was set to 200, peak sensitivity 30, and peak width 0.3 min.

QC analysis 5

All purified compounds were analyzed by LC-MS analysis prior to registration. Two methods of detection were used, UV (DIAD) and ELSD.

Analytical reverse phase chromatography was performed on a Phenomenex Luna C18, 5 µm, HPLC column (30 x 4.6 mm id.) At room temperature using a Waters 1525 dual LC pump. The column flow rate was 2.5 ml / min. The mobile phase used was a binary acetonitrile / water buffered with 0.05% (vol / vol) ammonium acetate. Initial chromatographic conditions were set at 5% acetonitrile. The gradient time table was achieved by increasing the acetonitrile concentration to 95% for 3 minutes while maintaining an additional 0.5 minutes prior to reconditioning the column at 5% acetonitrile for a further 1.0 minute. A Waters 2488 dual wavelength detector was used to detect dual wavelengths of 225 nm and 254 run.

25 30 1026329-

90 I

OH I

Ex. Name Mass De- Rt I

tec I

___tor___ I

2- [3- (2 - {[(2R) -2- (6-I

aminopyridin-3-yl) -1

2-hydroxyethyl] -1

amino} -2-methyl-1

40 propyl) phenyl] -N- {3-454.24 ELSD 1.35 / l

HI

hydroxy-4-methoxy-1

phenyl) acetamide I

2- [3- (2 - {[(2R) -2- (6-I

aminopyridin-3-yl) -1

2-hydroxyethyl] -1

Η I

amino) -2-methyl-HCl

41 434.23 ELSD 1.3 Tl ^ I

propyl) phenyl] -N- (3- II 1 l

hydroxy-I

phenyl) acetamide I

2- [3- (2 - {[(2R) -2- (6-I

aminopyridin-3-yl) -1

2-hydroxyethyl] -1

amino} -2-methyl-11

42 468.19 ELSD 1.46 V S * I

propyl) phenyl] -N- (2-N 1

Η I

chloro-4-hydroxy

phenyl) acetamide I

1026329-I

91 2- [3- (2 - {[(2 R) -2- (6-aminopyridin-3-yl) -

2-hydroxyethyl] - T | J

43 amino) -2-methyl-478.26 ELSD 1.25 Jv o >> propyl) phenyl] -N- (4-hydroxy-3-methoxy-benzyl) acetamide____-2- 2- 3- (2 - {[(2R () amino-pyridin-3-yl) -2-hydroxyethyl] -0.0% amino-2-methyl-44526.22 ELSD 1.25.

propyl) phenyl] -N- [5- (ethylsulfonyl) -2-hydroxyphenyl] -acetamide] -2- £ 3— (2— £ [(2R) -2- (6-aminopyridin-3-yl) -

2-hydroxyethyl] OH

amino} -2-methyl-DAD: n 45 448.25 1.52 - -.

propyl) phenyl] -N- (2- 225

H

hydroxy-5-methyl-phenyl) acetamide 2- [3- (2 - {[(2R) -2- (6-

aminopyridin-3-yl) - H

HO Γ - Η 2-hydroxyethyl] - γ - (46 amino) -2-methyl-482.21 ELSD 1.55 C. propyl) phenyl] -N- (5- '- (

C 1 chloro-2-hydroxy-benzyl) acetamide 2 - 3 - (2 - {[(2R) -2- (6-aminopyridin-3-yl) - = = 2-hydroxyethyl]; ^ 47 amino) -2-methyl-510.26 ELSD 1.89 = N / N

propyl) phenyl] -N- (4 H

hydroxy-1,1'-biphenyl-3-yl) acetamide _____ 1026329-

92

I 2— [3— (2 - {[(2R) -2- (6- I

Aminopyridin-3-yl) -1

2-hydroxyethyl] -1

Amino] -2-methyl-HO-1

48 propyl) phenyl] -N- [2-492.27 ELSD 1.25 L

1 hydroxy-2- {3-I

Hydroxyphenyl) ethyl]

N-methyl-raceetamide I

I 2- [3- (2 - {[(2R) -2- (6- I

Aminopyridin-3-yl) -1

2-hydroxyethyl] -1

I HO 'I

amino} -2-methyl-DAD: I

I 49 462.26 1.45 NLG 7

Propyl) phenyl] -N-255 · I

Ethyl N- (3-hydroxy-1

Phenyl) acetamide I

I 2— [3— (2 - {[(2R) -2- (6-. I

Aminopyridin-3-yl) -1

2-hydroxyethyl] -v. ^ I

I 1 N I

I amino} -2-methyl-I

50 propyl) phenyl] -N- [2-506.29 ELSD 1.4]

I (3-ethoxy-4 HO)

Hydroxyphenyl) ethyl]

Acetamide I

I 2- [3- (2 - {[(2R) -2- (6- I

Aminopyridin-3-yl) -1

2-hydroxyethyl] -1

1 amino) -2-methyl-1

Propyl) phenyl] -N-1

51 {[4 '- (hydroxymeth-538.29 ELSD 1.49 H I

11 yl) -1,1'-biphenyl-3-l

[Yl] methyl] acetamide I

LI_INI_ I

1026329-I

93 2- [3- {2 - {[(2R) -2- (6-aminopyridin-3-yl) -2-hydroxyethyl] -

C 1 -C 18 amino) -2-methyl-γχ

DAD: H

52 propyl) phenyl] -N- 516.17 1.9 U.mu. (2,4-dichloro-6-).

OH

hydroxybenzyl) acetamide 2— [3— (2— {f (2R) -2- (6-

aminopyridin-3-yl) - P

2-hydroxyethyl] - x Λ A

amino) -2-methyl-1 | 53 propyl) phenyl] -N- [(3- 542.27 ELSD 1.59 fluoro-4'-hydroxy-1,1'-biphenyl-4-yl) methyl] acetamide 2- (3- (2- ( [(2R) -2- (6-aminopyridin-3-yl) -2-hydroxyethyl] -.

amino) -2-methyl-4-propyl) phenyl] -N-1 HI 54 548.29 ELSD 1.7 [(4'-hydroxy-3-methyl-1,1'-biphenyl-4-yl) methyl] acetamide 2- [3- (2 - ([(2R) -2- (6-aminopyridin-3-yl) - -2-hydroxyethyl] amino) -2-methyl-DAD: CK /.

55 propyl) phenyl] -N- (2- 510.24, 1.67, 255

chloro-5-hydroxy-U / JL

. n "OH

benzyl) -N-ethylacetamide 1026329-I 94 I 2- [3- (2 - {[(2 R) -2- (6-aminopyridin-3-yl) -1-2-hydroxyethyl] -1-amino) -2) -methyl-T1 56 propyl) phenyl] -N-524.28 ELSD 1.73 I [(2'-hydroxy-1,1 '- 1 Jl'-biphenyl-2-yl) methyl] acetamide I 2 - [3- (2 - {[(2R) -2- (6-

Aminopyridin-3-yl) -1

F p 2-hydroxyethyl] - \ sr I / \. / \

amino) -2-methyl-p J 1 N

57 propyl) phenyl] -N- [3 - 530.25 ELSD 1.77 µl

Hydroxy-5- (trifluoro-1)

OH

1 methyl) benzyl] -N-methylacetamide I 2- [3- (2 - {[(2 R) -2- (6-amino-pyridin-3-yl) -

2-hydroxyethyl] -1

amino} -2-methyl-1-propyl) phenyl] -N- {3- [

58 510.24 ELSD 1.65 JL

chloro-5-hydroxy / f

Benzyl) -N-S

ethylacetanu.de I 2 - [3 - (2 - {[(2R) -2- (6-aminopyridin-3-yl) - 1 - 2-hydroxyethyl] -

I amino} -2-methyl-I

59 propyl) phenyl] -N- (3- 482.21 ELSD 1.52) chloro-5-hydroxy-benzyl) acetamide 1026329-95 2— [3 - (2 - {[(( 2 R) -2- (6-aminopyridin-3-yl) -2-hydroxyethyl] amino) -2-methyl-Tl 60 60 476.28 ELSD 1.49 N propyl) phenyl] -N- (4 u

HI

hydroxy-3,5-l

dimethylbenzyl) acetamide 2- [3- (2- {[(2R) -2- (6- (4-anunopyndin-3-yl) -2-hydroxyethyl] -f

61 amino) -2-methyl-262.26 ELSD 1.46

propyl) phenyl] -N- [2- | 1 (2-hydroxyphenyl) ethyl] acetamide _____ 2- [3- {2 - {[(2R) -2- (6-aminopyridin-3-yl) -2-hydroxyethyl] amino) -2-methyl- 62 524.3 ELSD 1.75 propyl) phenyl] -N- | | benzyl-N- (4-hydroxyphenyl) acetamide _____ 2- [3- (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -

H

2-hydroxyethyl] -

63 amino) -2-methyl-462.3 ELSD 1.26 ij T

propyl) phenyl] -N- [2- (4-hydroxyphenyl) - ethyl] acetamide____ 2 - {3 - (2 - {[(2R) -2- (6-aminopyridin-3-yl) -2-hydroxyethyl] -

64 amino) -2-methyl-448, 3 ELSD 1.33 µl

propyl) phenyl] -N- (4-hydroxybenzyl) acetamide-amide____-1026329-96 2- [3- {2 - {((2R) -2- (6-arainopyridin-3-yl) -1-)

2-hydroxyethyl] -1

65 araino) -2-methyl-448.3 ELSD 1.38 I propyl) phenyl] -N- (2-hydroxybenzyl) acetamide amide 2- (3- (2 - (((2R) -2- (6 - H-aminopyridin-3-yl) - 2-hydroxyethyl] -

H Tl N

66 amino} -2-raethyl-448.3 ELSD 1.33 || \ H

Propyl) phenyl] -N- (3-hydroxybenzyl) acetal H-amamide____-2- (3- (2 - (((2R) -2- (6- '))

aminopyridin-3-yl) - H

JsL

2-hydroxyethyl]-yT v χ I 67 amino) -2-methyl-462.3 ELSD 1.41> [y] H-propyl) phenyl] -N- [2- H (3-hydroxy-phenyl) -ethyl] acetamide______ I 2- (3- (2 - (((2R) -2- (6-aminopyridin-3-yl) - |

2-hydroxyethyl] -

amino) -2-methyl-1 / | χ

68 492.3 ELSD 1.29 ii J

propyl) phenyl] -N- (2- (4-hydroxy-3-methoxyphenyl) ethyl] acetamide____-methyl-4 - ({[3- (2- I {[(2R) -2- ( 6-amino.

Pyridin-3-yl) -2- χ

1 hydroxyethyl] -O II

69 492.2 ELSD 1.57 | amino) -2-methyl pro-

N

pyl) phenyl] ac-H

TylJamino) -3-hydroxybenzoate 1026329-97 2- [3- (2 - {[(2R) -2- (6-aminopyridin-3-yl) -2-hydroxyethyl] amino) -2-methyl- \\ 70 490.3 ELSD 1.85 \

propyl) phenyl] -N- (5-OH

tert-butyl-2 HN-4-hydroxy-phenyl) acetamide ______ 2- [3- (2 - {[(2 R) -2- (6-aminopyridin-3-yl) -2-hydroxyethyl] - HQ \\ 71 amino } -2-methyl- 448,3 ELSD 1.54-propyl) phenyl] -N- (3-hydroxy-4-methyl-phenyl) acetamide-OH h 5 ^

Ex. Name Mass De-Rt detector _____ 2- [3 - ((2R) -2 - {[(2R) -2- (6-aminopyridin-3-yl) -2-hydroxyethyl) -1-amino) propyl] phenyl] -

N- [2- (4-hydroxy-II)

72 448.25 ELSD 1.3 Λ

phenyl) ethyl] -acetate-HO

amide 1026329-198 I 2-13 - ({2 R) -2 - {[{2 R) - 2- (6-aminopyridin-3-yl) -2-hydroxyethyl] - HOvyl.

I 73 aminopropyl) phenyl] - 434.23 ELSD 1.16 II I H

N- (4-hydroxybenzyl) - acetamide I 2- [3 - ((2R) -2 - {[(2R) -2- (6-aminopyridin-3-)

I QH

yl) -2-hydroxyethyl] -

I DAD: JL

74 aminopropyl) phenyl] -434.23 1.35 M 225 ...

N- (2-hydroxybenzyl) - U

Acetamide I 2- [3 - ((2R) -2 - {[(2R) -2- (6-Arainopyridin-3-yl) -2-hydroxyethyl] -

75 aminopropyl) phenyl] - 434.23 ELSD 1.23 J | Λ H

N - (3-hydroxybenzyl) - acetamide 2- [3 - ((2R) -2 - {[(2R) -1 - 2- (6-aminopyridin-3-yl) -2-hydroxyethyl] - d

aminopropyl) phenyl] - T

76 448.25 ELSD 1.34 Η N- [2- (3-hydroxyphenyl) ethyl] acetamide I 2- [3 - ({2R) -2 - {[(2R) -1] 2- ( 6-aminopyridin-3-yl) -2-hydroxyethyl] - (Aminopropyl) phenyl) -J 77 778,26 ELSD 1,24 II - N- [2- (4-hydroxy-3-methoxyphenyl) ethyl] acetamide I 1026329-99 2- [3 - ((2R)) -2- {t (2R) -2- (6-aminopyridin-3-, yi) -2-hydroxyethyl] amino} - u.

78 476.28 ELSD 1.82 OH

propyl) phenyl] -N- (5- tert-butyl-2-hydroxyphenyl) acetamide 2- [3 - ((2R) -2- {[(2R) -2- (6-aminopyridin-3-) yl) -2- DAD: || ^ 79 hydroxyethyl] amino} - 434.23 1.52 255 propyl) phenyl] -N- (3- ^ hydroxy ^ 4-methylphenyl) acetamide 2 - [3 - ((2R) -2 - {[(2R) - 2- {6-aminopyridin-3-> y "-2- 80 hydroxyethyl] amino} - 450.23 ELSD 1.25 \ - / ^

propyl) phenyl] -N- (3-HO

hydroxy-4-methoxyphenyl) acetamide _____ 2- [3 - ((2R) -2 - {[(2R) -2- (6-aminopyridin-3-yl) -4]

y1 ’· 2H

81 hydroxyethyl] amino} - 464.24 ELSD 1.3

9 ^ X

propyl) phenyl] -N- (4- | hydroxy-3-methoxy-benzyl) acetamide 2- [3 - ((2R) -2 - {[(2R) -2- (6-aminopyridin-3-yl) -) 2-O hydroxyethyl] amino} - O 4 - Y ----- / 82 512.21 ELSD 1.22 \\

propyl) phenyl] -N- [5- / V qH

{ethylsulfonyl) -2-hydroxyphenyl] acetamide-1026329-100 I 2- [3 - ((2R) -2 - {[(2R) - Η 2- (6-aminopyridin-3-

III) -2-hydroxyethyl] -S-OH

I 83 aminopropyl) phenyl] - 434.23 ELSD 1.47 N- (2-hydroxy-5- "" "" * ""

I H

methyl-phenylacetate-2-anti-2-1-3 - ((2R) -2 - {[H 2- (6-aminopyridin-3, 1 H 1

yl) -2-hydroxyethyl] ur 1 U

DAD: ^ VV'V

84 aminopropyl) phenyl] 434.23 1.24 II

225 II J

N- (3-hydroxy-2-)

Methyl (phenyl) acetyl

I __amide_____ 2— [3 - ((2R) -2 - {[| 2R) -

2- (6-aminopyridin-3- |

III) -2-hydroxyethyl] -1

85 aminopropyl) phenyl] 468.19 ELSD 1.5

N-r <5-chloro-2-%

Hydroxybenzyl) - Q1

I-acetamide_____I

I 2- [3 - ((2R) -2 - {[(2R) -

2- (6-aminopyridin-3-OH)

III) -2-hydroxyethyl] - N.

86 amino-propyl) phenyl] - 478.26 ELSD 1.26 (I +)

N - [2-hydroxy-2- (3- I

Hydroxyphenyl) ethyl]

I-N-methyl-acetamide I

I 2- [3 - ((2R) -2 - {[(2R) -2- (6-aminopyridin-3- |

yl) -2-hydroxyethyl] -1

aminopropyl) phenyl] -1

DAD: Tl

87 N- [2- (3-ethoxy-4- 492.27 1.35] [I

225

hydroxy-phenyl) -> I

ethyl] acetamide I

1026329- 101 2- [3 - ((2R) -2 - {[(2R) -2- (6-aminopyridin-3-)

HO

yl) -2-hydroxyethyl) - 88 amino} propyl) phenyl] - 478.26 ELSD 1.29 J - - /

O - // \ N

N- [2- (3-hydroxy-4-methyl-methoxy-phenyl) -ethyl] acetamide _____ 2- [3 - {(2R) -2- {t (2R) -2- (6-aminopyridin) -3-yl) -2-hydroxyethyl] - 89 amino} propyl) phenyl] - 476.28 ELSD 1.52 µl N-ethyl-N- [2- (4- '

HO

hydroxyphenyl) - ethyl] acetamide _____ 2- [3 - ((2R) -2 - {[(2R) - 2- (6-aminopyridin-3-N.

yl) -2-hydroxyethyl] II

90 amino} propyl) phenyl] - 496.22 ELSD 1.56 N- (2-chloro-4 Cl hydroxybenzyl) -N- ethyl ethylacetamide_____ 2- [3 - ((2R) -2 - {[(2R) -

2- (6-aminopyridin-3 X

HN

yl) -2-hydroxyethyl] -1

amino} propyl) phenyl] -7 91 474.26 ELSD 1.36 N- (5-hydroxy-L-JL ^ 1,2,3,4-tetrahydro-).

OH

naphthalen-1-yl) acetamide amide 2- [3 - ((2R) -2 - {[(2R) -

OH

2- {6-aminopyridin-3-Y

yl) -2-hydroxyethyl] -amino) propyl) phenyl] -11 92 420.22 ELSD 1.19 N- (4-hydroxyphenyl) - | acetamide HN ^ 1026329-1 102 - - - - HN - 2- [3 - ((2R) -2 - {[(2R) - \ B 2- {6-aminopyridin-3-yl] -2-hydroxyethyl] - / DAD: (..

93 aminopropyl) phenyl] 476.28 1.42 255 N- [4- (4-hydroxy-Π)

phenyl) butyl] aceto-U

| amide] | ________ - 'OH - 2- (3 - ((2R) -2 - {[(2R) -1 - 2- (6-aminopyridin-3-yl) -2-hydroxyethyl] - Λ / = \ HO - \' ) —L,) - v.

94 aminopropyl) phenyl] - 510.26 ELSD 1.51 - - / - - - -> - N - [{4 '- hydroxy - 1,1' - biphenyl - 4 - yl) - methyl - acetyl amide_____ 2- [3 - ((2R) -2 - {[(2R) -1- (6-arainopyridin-3-yl) -2-hydroxyethyl] -

aminopropyl) phenyl] - N

95 524.28 ELSD 1.53 T II H

B N - {[4 '- (hydroxy-5 / methyl) -1,1'-bi-B phenyl-3-yl] methyl) - B-acetamide {2- [3 - ((2R) -2-) {[(2 R) - B 2- (6-aminopyridin-3- ^ ^

III) -2-hydroxyethyl] -1

96 aminopropyl) phenyl] -502.15 ELSD 1.74

N - (2,4-dichloro-6-)

B hydroxybenzyl) - B - acetamide - 2- (3 - ((2R) -2 - {[(2R) - B 2- (6-aminopyridin-3-yl) -2-hydroxyethyl] - \

I (aminopropyl) phenyl] 11

B 97 528.25 ELSD 1.64 N - [(3-fluoro-4 '-)

Hydroxy-1,1'-bi

phenyl-4-yl) methyl] -

acetamide I

10 [026329] 103 2- [3 - ((2R) -2 - {[(2R) -2- (6-aminopyridin-3-)].

yl) -2-hydroxyethyl] aminopropyl) phenyl] - 98 524.28 ELSD 1.59 1

N - [(4'-hydroxy-3-I | T

methyl 1,1'-biphenyl-4-yl) methyl] acetamide 2- [3 - ((2R) -2 - {[(2R) -

2- (6-aminopyridin-3-)

.NL / yl) -2-hydroxyethyl] - 99 aminopropyl) phenyl] - 496.22 ELSD 1.7 N- (2-chloro-5- hydroxybenzyl) -N-ethyl-acetamide ______. 2- [3- ( (2R) -2 - {[(2R) -2- (6-aminopyridin-3-yl) -2-hydroxyethyl] -1] 100 aminopropyl) phenyl] - 510.26 ELSD 1.61 ^

H

N- [(2'-hydroxy-1> 1'-biphenyl-2-yl) - methyl] acetamide. 2- [3 - {(2 R) -2- {t (2 R) -2- (6-aminopyridin-3-yl) -2-hydroxyethyl] -

• Tl N

aminopropyl) phenyl] II

101 516.23 ELSD 1.69 N- [3-hydroxy-5-

(trifluoro-methyl) - OH

benzyl) -N-methyl-acetamide _____ 2- [3 - ((2R) -2 - {[(2R) - *

2- (6-aminopyridin-3-)

.NL / yl) -2-hydroxyethyl] -12 102 aminopropyl) phenyl] -496.22 ELSD 1.6 N- (3-chloro-5-yl hydroxybenzyl) -N-ethyl-acetamide-1026329-I 104 I 2- [ 3 - ((2R) -2 - {[(2R) - 1- [2- (6-aminopyridin-3-yl] -2-yl) -2-hydroxyethyl] -1,13-aminopropyl) phenyl] -468.2 ELSD 1 , 4

N - (3-chloro-5- II

1 hydroxybenzyl) - Cl OH

I-acetamide____ I 2- [3 - ((2R) -2 - {[(2R) - | I 2- (6-aminopyridin-3

III) -2-hydroxyethyl] -4 N

Μ H

104 aminopropyl) phenyl] 462.3 ELSD 1.35 N- (4-hydroxy-3, 5-dimethylbenzyl) acetamide_____ 2- 2- [3 - ((2R) -2 - {[(2R ) -

I H

2- (6-aminopyridin-3-ylmethyl) -2-hydroxyethyl) - 105 amino} propyl) phenyl] - 502.2 ELSD 1.76

N- {3,5-dichloro-2-II

Hydroxybenzyl) - C1 Cl I acetacamide _____ I 5 I 10 I 15 I 1026329-105

HjjN ^ NT

Ex. Name Mass Detect.

____ tor__ 3— {2 - {[(2R) -2- (6-aminopyridin-3)

yl) -2-hydroxy-H

ethyl] -amino} -2- (106 methyl-propyl) -N-448.25 ELSD 1.26

HO

[2- (4-hydroxyphenylethyl) benzamide 3- (2 - {[(2R) -2- (6-aminopyridin-3-yl) -2-hydroxyethyl] -amino} -2-Tl] u 107 434.23 ELSD 1.34 Π µm methyl propyl) -N- (4-hydroxybenzyl) benzamide 3- (2 - {[{2R) -2- (6-aminopyridin-3-)

yl) -2-hydroxy-OH

ethyl) -amino} -2- 1 year (108 methyl-propyl) -N-434.23 ELSD 1.43 (1-year) (2-hydroxybenzyl) benzamide 12.2329) I 106 I 3- (2 - ([(2R) -2- (6-aminopyridin-3-yl) -2-hydroxy-ethyl) -amino} -2-] 109,475.25 ELSD 1.32 (IJ.

H methyl-propyl) -N- '(2- (3-hydroxyphenyl) ethyl] benzamide____ 3- (2 - ([(2R) -2- (6-aminopyridin-3-yl)) - 2-hydroxy

u O ^ H

ethyl] -amino} -2-

110 methyl-propyl) -N-478.26 ELSD 1.4

I [2- (4-hydroxy-3-H2 methoxyphenyl) ethyl] benzamide 3- (2 - ([(2 R) -2- {6-aminopyridin-3-yl) -2-hydroxy-

| | - I I

ethyl] -amino) -2-n'O

11 111 methyl-propyl) -N-434.23 ELSD 1.44 J (3-hydroxy-4-methyl-phenyl) -H benzamide 3- (2 - {[(2R) -2- (6-aminopyridin-3)) -

I ,, o you. OH

yl) -2-hydroxy- Ethyl] -amino} -2-methyl-propyl) -N- [^. Ij

112 [2- (4-hydroxy-508.27 ELSD 1.34 H)

3,5-dimethoxyphenyl) ethyl] benzamide I 1026329 107 3- (2 - ([(2R) -2- (6-aminopyridin-3-yl) -2-hydroxyethyl] - amino} -2- \ fi \ /

Orn 'v — N

113 methyl-propyl) -N-450.23 ELSD 1.27 \ / h (3-hydroxy-4-methoxyphenyl) -benzamide 3- (2 - ([(2R) -2- {6-aminopyridin-3-

yl) -2-hydroxy-HO 2 M

ethyl] -aniino} -2-11 T ^

114 420.22 ELSD 1.4 [I J

methyl-propyl) -N- (3-hydroxyphenyl) -benzamide 3- (2 - ([(2R) -2- (6-aminopyridin-3-yl) -2-hydroxy-1-yl)

ethyl] -amino) -2- || > | H

methyl-propyl) -N-115 464.24 ELSD 1.25 O ^ (4-hydroxy-3-methoxybenzyl) -benzamide 3- (2 - (((2R) -2- (6-aminopyridin-3-)

yl) -2-hydroxy-H

ethyl] -amino} -2-, P

xrV

methyl propyl) - N - 116 512.21 ELSD 1.24 - (5- (ethylsulfonyl) -2-hydroxyphenyl) benzamide 1026329 - 108 - 3- (2- { [(2R) -2- (6-aminopyridin-3-yl) -2-hydroxy-11-methyl] -propyl) -N-434.23 ELSD 1.26 (3-hydroxy-2-) methyl phenyl) benzamide 1 3- (2 - {[(2R> -2- (6-aminopyridin-3-)

III) -2-hydroxyHQ H

Ethyl] -amino) -2- (methyl-propyl) -N-4 68.19 ELSD 1.69 ^ {5-chloro-2- '- \

C 1 hydroxy-benzyl) -benzamide 3 - <2 - {[(2R) -2- (6-aminopyridin-3-yl) -2-hydroxy-, Γ === \ ethyl] -amino) -2- (119) methyl-propyl) -N-496.25 ELSD 1.84 HN - "

(4-hydroxy-1,1'-H

I biphenyl-3-yl) -benzamide 3- (2 - {[(2R) -2- (6-aminopyridin-3-yl) -2-hydroxy-1 OH-1-ethyl] -amino) -2- HO 2 Methyl propyl) -N-β

120 478.26 ELSD 1.29 // / N

[2-hydroxy-2- (3-hydroxyphenyl) -ethyl] -N-methyl-benzamide I 1026329-109 3- {2 - {[(2R) -2- (6-aminopyridin-3-yl) -2 -hydroxy-ethyl] -amino} -2- 121 methyl-propyl) -N-448.25 ELSD 1.43 Γ II |

(2-hydroxy-OH

benzyl) -N-methyl-benzamide 3- (2 - {[(2R) -2- (6-aminopyridin-3-

H

yl) -2-hydroxy-ethyl] -amino} -2-

DAD: OH

122 methyl propyl) -N-502.15 1.82 sf 225 II | (3,5-dichloro-2-hydroxybenzyl) -4-benzamide 3- (2 - ([(2R) -2- (6-aminopyridin-3-)

yl) -2-hydroxy HN

ethyl] -amino) -2-

123 methyl-propyl) -N-448.25 ELSD 1.41 I

[2- (2-hydroxyphenyl) ethyl] benzamide 3- (2 - ([(2R) -2- (6-aminopyridin-3-yl) -2-hydroxy-.

ethyl] -amino) -2- \

O

methyl-propyl) -N- / 124 492.27 ELSD 1.34 v /

[2- (3-ethoxy-4- [alpha] - (f-y-OH

hydroxyphenyl) - ethyl] benzamide 1026329-110

I 3- (2 - {[(2R) -2- (6- I

Aminopyridin-3

III) -2-hydroxy-III

Ethyl] -amino} -2-vy

125 478.26 ELSD 1.09 / l

Methyl propyl) - N -) -

I [2- (3-hydroxy-4 HO)

methoxyphenyl) -1

Ethyl benzamide I

I 2— £ 3— (2 - {[(2R) -2- I

(6-aminopyridine)

1 3-yl) -2-hydroxy-1

Ethyl] -amino) -2-

I 126 474.26 ELSD 1.28 I

ethyl propyl) -

Benzoyl-1,3,4,5- *. I

I tetrahydro-1H-2-I

Benzazepin-8-ol ______._ I

I 3- (2 - {[(2R) -2- (6- I

Aminopyridin-3

III) -2-hydroxy-III

Ethyl] -amino} -2-y I

127 methyl-propyl) -N-524.28 ELSD 1.48 HN rf

I '-V V— (f vS — ΠΗ I

I [(4 '-hydroxy-3- \ / \ _ / I

Methyl-1, 1'-bi-1

Phenyl-4-yl) -1

Methyl methyl benzamide I

I 3— (2 - {[(2R) -2- (6- I

Aminopyridin-3

III) -2-hydroxy-III

Ethyl] -amino} -2- = C. ^ I

128 methyl-prop-opyl) - 510.26 ELSD 1.25 H ° / / / /

N - [(3'-hydroxy-1

1,1'-biphenyl-2-

I-yl) -methyl] -I

Benzamide_____I

I 1026329-111

OH O

Ex. Name Mass Detector R ____ tor 3 - ((2R) -2 - {[(2R) - 2- (6-aminopyridin).

3-yl) -2-hydroxy-HO 4 f ~ N

ethyl] -amino} - / - 129 454.2 ELSD 1.63 / -> propyl) - N - {5- {chloro-2-hydroxy-C 1 benzyl) benzamide.

3 - ((2R) -2 - {[(2R) - 2- {6-aminopyridin-3-yl) -2-hydroxyethyl] -amino} -propyl) -N- [2- 130 464.2 ELSD 1.25 J / hydroxy-2- (3- N.

hydroxyphenyl) - ethyl] -N-methyl-benzamide 3- {(2R) -2 - {[(2R) -2- (6-aminopyridinyl / v)

3-yl) -2-hydroxy-N

ethyl] -amino} - L11

131 434.2 ELSD 1.4 propyl) -N- (2-hydroxybenzyl) -N-methylbenzamide 1026329-1 112 3 - ((2R) -2 - {[(2R) - Η 2- (6-aminopyridin) 3-yl) -2-hydroxy-4 · ethyl] -amino} - (132 propyl) -N- [2- (3- 478.3 ELSD 1.36 I ethoxy-4-hydroxyphenyl) ethyl] -1 benzamide I 3 - ((2R) -2 - {[(2R) -2- (6-aminopyridin-3-yl) -2-hydroxy-1-).

Ethyl] -amino} -%% / I133 propyl) -N- [2- (3-464.2 ELSD1.39 '' ", hydroxy-4-methoxyphenyl) ethyl] -1 benzamide 2- [3 - ((2R) -2-] {[(2R) -2- (6-amino-pyridin-3-yl) -2- hydroxyethyl] -amino] -13-nopropyl; ) - 460.3 ELSD 1.39 ·

HO

benzoyl] -2,3,4,5-tetra I tetrahydro-1H-2-benzazepin-8-ol I 3 - ((2R) -2 - {[<2R) -1 - 2- (6-aminopyridin-3) -yl) -2-hydroxy.

Ethyl] -amino) -12 J, propyl) -N-ethyl-N-11

135 462.3 ELSD 1.45 M J

[2- (4-hydroxyfe-HO.)

methyl) ethyl] benzamide 1026329-1133 - ((2R) -2 - {[(2R) -2- (6-aminopyridin-3-yl) -2-hydroxy-HO].

ethyl] -amino} - NS N

136 482.2 ELSD 1.49 propyl) -N- (2-chloro-4-hydroxybenzyl) -N-ethyl-benzamide 3 - {(2R) -2 - {[(2R) -2- (6 -aminopyridin-Hh!

3-yl) -2-hydroxy-1

ethyl] -amino} - fl 'ίΓ

137 460.3 ELSD 1.48 I

propyl) -N- (5-

hydroxy 1,2,3,4-l

OH

tetrahydronaphthalen-1-yl) benzamide _____ 2- {4- [3 - ((2R) -2- {[2R) -2- (6-amino-pyridin-3-yl) -2-hy-] / / (N / N - 138 droxethyl) - 475.3 ELSD 1.46 (amino) propyl) - benzoyl) piperazin-1-yl) phenol _____

3- ((2R) -2- {[(2R) - OH

2- (6-aminopyridin-JL

3-yl) -2-hydroxy-139 ethyl] -amino) - 406.2 ELSD 1.24 propyl) -N- (4-hydroxybenzyl) -benzamide____-3- ((2R) -2- {[(2R ) - S *

2- (6-aminopyridin-J

3-yl) -2-hydroxy-

140 ethyljamino) - 462.3 ELSD 1.44 J

propyl) phenyl] -N- [4- (4-hydroxyphenyl) butyl] -_____ U Λ '__

OH

1026329-114

Benzamide I

I 3 - ((2R) -2 - ([(2R) -

2- (6-aminopyridine)

1 3-yl) -2-hydroxy-1

I ethyl] -amino) - μη-ΖΛ-ΓΊ) - v 141 4 96.3 ELSD 1.54 / \ //

propyl) -N- [(4'- '-' - h "~ *" I

1 hydroxy-1,1'-bi

Phenyl-4-yl) -1

Methyl] benzamide

I 3 - ((2R) -2 - {[

2- (6-aminopyridine)

3-yl) -2-hydroxy-1

Ethyl] -amino} - Η0 ^ | Γ ^] I

142 propyl) -N- [(4 '- 510.3 ELSD 1.54 L

I hydroxymethyl I

1,1'-biphenyl-3-

I-yl) methyl] benz-I

I __amide____ I

I 3 - ((2R) -2 - ([(2R) -

2- (6-aminopyridine)

1 3-yl) -2-hydroxy-q | qj I

Ethyl] -amino) -. | j | _j I

143 propyl) -N- (2,4- 488.1 ELSD 1.79 I

I dichloro-6-I

I (hydroxybenzyl) -1

Benzamide I

I 3 - ((2R) -2 - ([(2R) - I

2- (6-aminopyridine)

1 3-yl) -2-hydroxy-1

Ethyl] -amino} -1 / l

I I

Propyl) -N- [(3-I * "* I

144 514.2 ELSD 1.69 I

fluoro-4'-hydroxy-1

1,1'-biphenyl-4- I

I-yl) methyl] benz-I

I amide I

10 (1026329) 115 3- ((2R) -2- {U 2 R) -2- (6-aminopyridin-3-yl) -2-hydroxy-.

1 H

ethyl] -amino} -propyl) -N- [(4 '- JL J1 14550.3 ELSD 1.61 hydroxy-3-methyl-1,1'-biphenyl-4-yl) methyl] benzamide 3- ( (2R) -2 - {[(2R) - 2- (6-aminopyridin-3-yl) -2-hydroxy-ethyl] -amino) -

146 propyl) -N- (2- 482.2 ELSD 1.63 ql)

chloro-5-hydroxy benzyl) -N-ethyl-

> * OH

benzamide 3 - ((2R) -2- {[(2R) -2- (6-arainopyridin-3-yl) -2-hydroxy-ethyl] -amino) -141 propyl) -N- [(2'- 496 3 ELSD 1.64

hydroxy 1,1'-bi- [| H

phenyl-2-yl) - x methyl] benzamide 3 - ((2R) -2- {t (2R) - 2- (6-aminopyridin)

3-yl) -2-hydroxy-4

ethyl] -amino) -

148 propyl) -N- [(4 '- 496.3 ELSD 1.59 | H

W \> NV

hydroxy-1,1 '- biphenyl-2-yl) -methyl] benzamide 1026329-1163 - ((2R) -2 - ([(2R) - Η 2- (6-aminopyridin-3-yl) -2-hydroxy

Ethyl] -amino) - F

I, propyl) -N- [3- 149 502.2 ELSD 1.65 T T 1 hydroxy-5- (tri- (I |

H fluoro-methyl) -1

Benzyl] -N-methyl-OH

H benzamide I 3 - ((2R) - 2 - [(2R) - 2- (6-aminopyridin-3-yl) -2-hydroxy-1-ethyl] -amino} - 1 150 propyl) - N - (3 - 482.2 ELSD 1.55 L chloro-5-hydroxy LI.

1 benzyl) -N-ethyl-benzamide I 3 - ((2R) -2 - {[(2R) -1] 2- (6-aminopyridin-3-yl) -2-hydroxy-

ethyl] -amino} -1

151 454.2 ELSD 1.44 propyl) -N- (3-yl chloro-5-hydroxybenzyl) benzamide 3 - ((2R) -2 - ([(2R) - 2- (6-aminopyridin-3 - yl) -2-hydroxy-

ethyl] -amino} -1

propyl) -N- [(4'-152 496.3 ELSD 1.63 ^] ü

hydroxy-1,1 '- L1) MI

biphenyl-3-yl) -1

methyl] benzamide I

1026329-1173 - ((2R) -2 - {[(2R) -2- (6-aminopyridin-3-yl) -2-hydroxyethyl] -amino} - II I ^ 153 448, 3 ELSD 1, 35

propyl) -N- (4-HO J

hydroxy-3,5-dimethylbenzyl) - benzamide____ 3 - ((2R) -2 - {[(2R) - 2- (6-aminopyridin-3-yl) -2-hydroxy-ethyl] -amino] - I now 154 488, 1 ELSD 1.88

propyl) -N- (3,5-Π T

dichloro-2-hydroxybenzyl) -benzamide 3- ((2R) -2 - {[(2R) - ^

2- (6-aminopyridin-HN

3-yl) -2-hydroxy-155 ethyl] -amino} - 434.2 ELSD 1.37 [HO.

propyl) -N- [2- (2- 11 hydroxyphenyl) - ethyl] benzamide _____ 3 - ((2R) -2 - ([(2R) - 2- (6-aminopyridin)

3-yl) -2-hydroxy-Q-N-N

156 ethyl] -amino) - 436.21 ELSD 1.23 V / propyl) -N- (3-HO c hydroxy-4-methoxyphenyl) benzamide____ 3 - ((2R) -2 - ([( 2R) - 2- (6-aminopyridin)

3-yl) -2-hydroxy-HO. N

157 ethyl] -amino) - 406.2 ELSD 1.31 propyl) -N- (3-hydroxyphenyl) -benzamide_____ ·· _ 1026329-1 118 I 3 - ((2R) -2 - ([(2R) -2) - (6-amino pyridine)

1 3-yl) -2-hydroxy-H

158 ethyl] amino} 450.23 ELSD 1.31

Propyl) -N- (4-T

1 hydroxy-3-methoxy-benzyl) benzamide I 3 - ((2R) -2 - {[(2R) - 2- {6-aminopyridin-1H i

3-yl) -2-hydroxy-O

Ethyl] -ami.no) -1

159 498.19 ELSD 1.17 / (propyl) -N- [5- - '

(ethylsulfonyl) -2-l

Hydroxyphenyl] benzyl

I-amide I

I 3 - ((2R) -2 - {[(2R) -

2- (6-aminopyridine)

1 3-yl) -2-hydroxy-1

160 ethyl] amino} 420.22 ELSD 1.57

IN-

propyl) -N- (2- Η I

1 hydroxy-5-methyl-1

I (phenyl) benzamide

I 3 - ((2R) -2 - {[(2R) -

2- (6-aminopyridine)

I 3-yl) -2-hydroxy-I

161 ethyl] -amino} - 420.22 ELSD 1.2 l

Propyl) -N- (3- l

1 hydroxy-2-methyl-1

Phenyl) benzamide I

I 3 - ((2R) -2 - {[(2R) - I

2- (6-aminopyridine)

I Hl

1 3-yl) -2-hydroxy-1

Ethyl] -amino) -ij | I

162 434.23 ELSD 1.25, I

Propyl) -N- [2- (4-HO 1

1 hydroxyphenyl) -1

Ethyl] benzamide I

I - 1026329-119 3 - ((2R) -2 - {[(2R) - 2- (6-aminopyridin-3-yl) -2-hydroxy-163-ethyl] -amino} - 420.22 ELSD 1.18 II J 11 propyl) - N - (4-hydroxybenzyl) - benzamide_____ 3 - ({2 R) -2- {f (2 R) -

2- (6-aminopyridin-OH

3-yl) -2-hydroxy-4

165 ethyl] -amino} - 420.22 ELSD 1.49 || H

propyl) - N - (2-hydroxybenzyl) - benzamide - 3 - ((2R) -2 - {[(2R) - 2- (6-aminopyridin-3-yl) -2-hydroxy-

168 ethyl] -amino} - 420.22 ELSD 1.23 (| Ί H

propyl) - N - (3-hydroxybenzyl) - benzamide {3 - ((2R) -2 - {[(2R) - 2- (6-aminopyridin)

u _H

3-yl) -2-hydroxy

169 ethyl] -amino} - 434.23 ELSD 1.34 [| J

propyl) -N- [2- (3-hydroxyphenyl) - ethyl] benzamide _____ 1026329-1 120 I Preparation 1: N-Benzyl-2- [3 - ((2R) -2 - {(2R) -2-) [6- (2,5-di-methyl-pyrrol-1-yl) -pyridin-3-yl-3-hydroxy-ethylamino} -1-propyl) -phenyl] -acetamide I 5 I ° H Η Η I | 1 I ίτ ^ ΝϊΎΥϊΝ I> ΝΛΝ ^ CH, o I 10 C {

I CHS

A solution of the acid in the preparation 21 (200 mg, I

0.41 mmol), o-benzotriazol-1-yl-Ν, Ν, Ν ', N'-tetramethyluro

Sodium hexafluorophosphate (114 mg, 0.48 mmol), triethylamine I

I (1.0 ml, 7.17 mmol) and benzylamine (52 mg, 0.48 mmol) in I

N, N-dimethylformamide (3 ml) was quenched for 40 hours

I dust atmosphere stirred at room temperature. The reaction I

I mixture was diluted with water (3 ml) and extracted with I

Ethyl acetate (2 x 10 ml). The combined organic ex

Tracts were dried (sodium sulfate) and under vacuum I

I evaporated to dryness. Purification by flash column chromatography

I Elution with dichloromethane: methanol: ammonia I

I (changing 100: 0: 0 to 94: 6: 0.5 by volume) gave the I

Title compound as a pale yellow oil (148 mg). I

1 H NMR (400 MHz, CD 3 OD): δ = 8.52 (1 H, s), 7.96 (1 H, d), I 7.30-7.09 (10 H, m), 582 (2 H, s ), 4.86 (1 H, m), 4.34 (2 H, 1 s), 3.53 (2 H, s), 3.01 (1 H, ra), 2.88 (2 H, m), 2, 80 (1 H, 1 m), 2.61 (1 H, m), 2.03 (6 H, s), 1.08 (3 H, d) ppm.

30 LRMS (APCI): m / z [M + H] + 497.

I 1026329-121

Preparation 2: 2- [3 - ((2R) -2 - {(2R) -2- [6- (2,5-Dimethyl-pyrrol-1-yl) -pyridin-3-yl] -2-hydroxy- ethylamino} -propyl) -phenyl] -N- (2-methoxy-benzyl) -acetamide 50 H 10 CH 3.

Prepared according to the method described for Preparation 1 using the appropriate amine to give the title compound 15 as a pale yellow oil.

X H NMR (400 MHz, CD3 OD): δ - 8.51 (1 H, s), 7.92 (1 H, d), 7.29-6.83 (9 H, m), 5.81 (2 H, s) ), 4.81 (1 H, m), 4.34 (2 H, s), 3.77 (3 H, s), 3.52 (2 H, s), 2.95 (1 H, s), 2.85 (2H, m), 2.74 (1H, m), 2.59 (1H, m), 2.03 (6H, s), 1.06 (3H, d) 2.0 ppm.

LRMS (APCI): m / z [M + H] + 527.

Preparation 3: 2- [3 - ((2R) -2 - {(2R) -2-16- (2,5-Dimethyl-pyrrol-1-yl) -pyridin-3-yl] -2-hydroxyethylamino } -propyl) -phenyl] -25 N- (2-ethoxy-benzyl) -acetamide H3c ιιιη T ü TH '30 L JL ^ CH3 Ks? O / O CH 3 ch 3 1026329 Prepared according to the method described for preparation 1 using the appropriate amine to give the title compound as a pale yellow oil.

122 I

1 H NMR (400 MHz, CD 3 O 6): δ = 8.50 (1H, s), 7.94 (1H, d), 1

7.29-6.80 (9H, m), 5.82 (2H, s), 4.83 (1H, m), 4.35 (2H, I)

s), 3.99 (2H, q), 3.52 (2H, s), 2.96 (1H, m), 2.85 (2H, I)

m), 2.76 (1 H, m), 2.55 (1 H, m), 2.03 (6 H, s), 1.33 (3 H, I)

5 t), 1.06 (3 H, d) ppm. I

LRMS (APCI): m / z [M + H] + 541. I

Preparation 4: 2- [3 - ((2R) -2 - {(2R) -2- [6- (2,5-Dimethylpyrrole)

1-yl) -pyridin-3-yl] -2-hydroxy-ethylamino} -propyl) -phenyl] -1

N- (3-phenyl-propyl) -acetamide I

h3C (11 L II

15 L .A A ch3 o I

^ CH3 I

Prepared according to the method described for preparation I

1 using the appropriate amine to give the title compound I

to give as a pale yellow oil. I

2 H NMR (400 MHz, CD 3 OD): δ = 8.52 (1 H, s), 7.94 (1 H, d), 1

7.28-7.08 (10 H, m), 5.82 (2 H, s), 4.82 (1 H, m), 3.47 (2 H, I)

25 s), 3.19 (2 H, m), 3.00 (1 H, m), 2.86-2.77 (3 H, m), 2.60-1

2.54 (3H, m), 2.03 (6H, s), 1.77 (2H, m), 1.05 (3H, d) I

ppm. I

LRMS (APCI): m / z [M + H] + 525. I

1026329-123

Preparation 5: Prepared from 2- [3 - ((2R) -2 - {(2R) -2- [6- (2,5-)

Dimethyl-pyrrol-1-yl) -pyridin-3-yl] -2-hydroxy-ethylamino} -propyl) -phenyl] -N-phenethyl-acetamide

5 OH η H

3 L JL GH3 KsJ O

α n 10 nch3

Prepared according to the method described for preparation 1 using the appropriate amine to give the title compound 15 as a pale yellow oil.

X H NMR (400 MHz, CD3 OD): δ = 8.51 (1 H, d), 7.95 (1 H, d), 7.29-7.08 (10 H, m), 5.81 (1 H, m) , 4.83 (1 H, m), 3.44 (2 H, s), 2.99 (1 H, m), 2.85 (3 H, m), 2.77 (4 H, m), 2.60 ( 1 H, m), 2.04 (6 H, s), 1.08 (3 H, d) ppm.

LRMS (APCI): m / z [M + H] + 511.

Preparation 6: N- (3,4-Dimethyl-benzyl) -2- [3 - ((2R) -2 - {(2R) -2- [6- (2,5-dimethyl-pyrrol-1-yl)] -pyridin-3-yl] -2-hydroxy-ethylamino) -propyl) -phenyl] -acetamide 25 OH η 30 CH 3

Prepared according to the method described for preparation 35 L using the appropriate amine to give the title compound as a pale yellow oil.

1026329-

I 124 I

1 X H NMR (400 MHz, CD 3 OD): δ - 8.55 (1 H, s), 7.95 (1 H, d), 1

I 7.32-6.90 (8 H, m), 5.81 (2 H, s), 4.90 (1 H, m), 4.25 (2 H, I)

S), 3.52 (2 H, s), 3.18 (1 H, m), 3.00 (2 H, m), 2.88 (1 H, I)

M), 2.65 (1H, m), 2.18 (6H, s), 2.02 (6H, s), 1 * 05 (3H, d) I

I 5 ppm. I

LRMS (APCI): m / z [M + H] + 525. I

Preparation 7: 2- [3 - ((2R) -2- {(2R) -2- [6- (2r5-Dimethylpyrrole-I

1-yl) -pyridin-3-yl] -2-hydroxy-ethylamino) -propyl) -phenyl] -1

10 N-idan-2-yl-acetamide I

H OH

I ίίΥ ^ Ν ^ ΎΎΥ ΧΥλ

I n c L & CH a o '- <r / I

I 15 N 3 = / I

I ^ ch3 I

Prepared according to the method described for preparation I

I 1 using the appropriate amine to give the title compound I

I give as a pale yellow oil. I

1 X H NMR (400 MHz, CD 3 OD): δ * 8.57 (1H, s), 8.00 (1H, d), I

I 7.33-7.10 (9 H, m), 5.82 (2 H, s), 4.94 (1 H, m), 4.55 (1 H, I)

25 m), 3.47 (2 H, s), 3.31-2.66 (9 H, m), 2.04 (6 H, s), 1.17 I

I (3 H, d) ppm. I

LRMS (APCI): m / z [M + HJ + 523. I

1026329 = I

125

Preparation 8: N- (3,4-Dichloro-benzyl) -2- [3 - ((2R) -2 - {(2R) -2- [6- (2,5-dimethyl-pyrrol-1-yl)] -pyridin-3-yl] -2-hydroxy-ethylamino} -propyl) -phenyl] -acetamide

5 XI

° H Η Η Γ Y '- K *

Prepared according to the method described for Preparation 1 using 3,4-dichlorobenzylamine as the amine to give the title compound as a pale yellow oil.

X H NMR (400 MHz, CD3 OD): δ 8.56 (1 H, s), 8.01 (1 H, d), 7.59-7.13 (8 H, m), 5.82 (2 H, s), 4.92 (1 H, m), 4.32 (2 H, s), 3.55 (2 H, s), 3.20 (1 H, m), 3.05 (2 H, m), 2.91 (1 H , m), 2.70 (1 H, m), 2.04 (6 H, s), 1.15 (3 H, d) ppm.

LRMS (APCI): m / z [M + H] + 541/543.

Preparation 9: 2- [3- (2 - {(2 R) -2- [6- (2,5-Dimethyl-pyrrol-1-yl) -pyridin-3-yl] -2-hydroxy-ethylamino] -propyl) -phenyl] -N- (4-hydroxy-3-methoxy-benzyl) -acetamide 25 v (Λ ^ γγγγ1 ^ 0'ο '"" "X 0 CH3

Prepared according to the method described for preparation 35 1 using the acid from preparation 30 and the appropriate amine to give the title compound as a pale yellow oil.

1026329-

126 I

* H NMR (400 MHz, CDCl 3): δ = 8.47 (1H, m), 7.78-7.75 (1H, 1

m), 7.28-7.24 (1 H, m), 7.17-7.08 (3 H, m), 6.86 6.61 (4 H, I)

m), 6.01-5.94 (3H, m), 4.72-4.57 (1H, m), 4.34-4.25 (2H, I)

m), 3.80 (3H, m), 3.58-3.56 (2H, m), 3.10-2.57 (5H> m), I

5 2.09 (6H, s), 1.13 (3H, t) ppm. I

LRMS (APCI): m / z [M + H} + 543, [M + Na] + 565, [M-H] "541. I

Preparation 10; 2- [4- (2 - {(2 R) -2- [6- (2,5-Dimethyl-pyrrole-11)

yl) -pyridin-3-yl] -2-hydroxy-ethylamino} -2-methyl-propyl) -1

Phenyl] -N- (3-methoxy-benzyl) -acetamide I

° H Η I

h c o I

15 JL h3cch3I! ^ IL · ji ^ I

<(J "3 3 ch3 I

^ ch3 I

Prepared according to the method described for preparation I

1 using the acid from preparation 36 and the suitable l

too amine to give the title compound as a pale yellow I

foam. I

1 H NMR (400 MHz, CDCl 3): 6 - 8.58 (1 H, s), 7.82 (1 H, d), 1

25 7.20 (4H, m), 7.18 (2H, m), 6.78 (2H, m), 6.72 (1H, s), I

5.98 (1H, bs), 5.85 (2H, s), 4.62 (1H, dd), 4.38 (2H, d), I

3.72 (3H, s), 3.58 (2H, s), 3.00 (1H, dd), 2.65 (3H, m), I

2.08 (6H, s), 1.11 (3H, s), 1.10 (3H, s) ppm. I

LRMS (APCI): m / z [M + H] + 541. I

30 I

1026329-I

127

Preparation 11: N- (2,6-Dimethoxy-benzyl) -2- [4- (2 - {(2 R) -2- [6- (2,5-dimethyl-pyrrol-1-yl) -pyridin-3 -yl] -2-hydroxy-ethylamino} -2-methyl-propyl) -phenyl] -acetamide 5 ·.

OH

, N. "CH,

HjC \ CY ^ * 7Cf \ 1? -o ga · ch3

Prepared by the method described for Preparation 1 using the acid from Preparation 36 and the suitable amine to give the title compound as a pale yellow solid.

X H NMR (400 MHz, CDCl 3): δ = 8.58 (1 H, s), 7.90 (1 H, d), 7.20-7.10 (6 H, m), 6.50 (2 H, d) , 6.00 (1 H, s), 5.90 (2 H, S), 4.70 (1 H, dd), 4.50 (2 H, d), 3.73 (6 H, s), 3.50 ( 2 H, 20 s), 3.05 (1 H, dd), 2.72 (3 H, m), 2.10 (6 H, s), 1.11 (3 H, s), 1.10 (3 H, s) ppm.

LRMS (APCI): m / z [M + H] + 571.

Preparation 12: 2- [3- (2 - {(2 R) -2- [6- (2,5-Dimethyl-pyrrol-1-yl) -pyridin-3-yl] -2-hydroxy-ethylamino} - 2-methyl-propyl) -phenyl] -N- (4-sulfamoyl-benzyl) -acetamide OH ^ γδ02ΝΗ2 30 Th h h3c ίΎ ^ Ν> ΛίΥΥΝ ^

L h3 C ch3 S

CH, 02 63 29-

Prepared according to the method described for preparation 1 using the acid from preparation 34 and the suitable 35

128 I

too amine to give the title compound as a pale yellow I

solid. I

* H NMR (400 MHz, CD3 OD): δ = 8.58 (1H, s), 8.03 (1H, d), I

7.79 (2H, d), 7.37 (2H, d), 7.31 (1H, d), 7.23 (1H, d), I

5 7.18 (2H, m), 7.13 (1H, d), 5.82 (2H, s), 4.81 (1H, given)

partially shaded by solvent), 4.42 (2H, s), I

3.56 (2H, s), 2.91-2.88 (2H, m), 2.78-2.66 (2H, m), 2.04 I

(6H, s), 1.07 (3H, s), 1.04 (3H, s) ppm. I

LRMS (APCI): m / z [M + H) + 590, [M-H] "588. I

10 I

Preparation 13: 2- [3- (2 - {(2 R) -2- [6- (2,5-Dimethyl-pyrrol-1-)]

yl) -pyridin-3-yl] -2-hydroxy-ethylamino} -2-methyl-propyl) -1

phenyl] -N- (2-ethoxy-benzyl) -acetamide I

I

° h η η n 1

20 \ = A

CH3 I

Prepared according to the method described for preparation I

1 using the acid from preparation 34 and the suitable l

Too amine to give the title compound as a pale yellow I

solid. I

X H NMR (400 MHz, CD3 OD): δ - 8.58 (1 H, s), 8.02 (1 H, d), I

7.30 (1H, d), 7.25-7.10 (5H, m), 6.91-6.80 (3H, m), 5.80 l

(2H, s), 4.92 (1H, 'partially shaded by solution

Medium), 4.38 (2 H, s), 4.02 (2 H, q), 3.55 (2 H, s), 2.90-1

2.82 (2H, m), 2.78-2, 65 (2H, m), 2.03 (6H, s), 1.03 (3H, I)

t), 1.05 (3 H, s), 1.04 (3 H, s) ppm. I

LRMS (APCI): m / z [M + H] + 555. I

1026329-5 129

Preparation 14: 2- [3- (2 - {(2 R) -2- [6- (2,5-Dimethyl-pyrrol-1-yl) -pyridin-3-yl] -2-hydroxy-ethylamino} -2 -methyl-propyl) -phenyl] -N-indan-2-yl-acetamide

° H Η H

h3q H »C CH3 G> L = / ^ CH3>

Prepared by the method described for Preparation 1 using the acid from Preparation 34 and the suitable amine to give the title compound as a pale yellow oil.

* H NMR (400 MHz, CD3 OD): δ - 8.58 (1 H, s), 8.05 (1 H, d), 7.30 (1 H, d), 7.25-7.08 (8 H, m ), 5.81 (2 H, s), 4.55 (1 H, m), 3.47 (2 H, s), 3.25 (1 H, d), 3.20 (1 H, d), 2.98 -2.90 (7H, m), 2.00 (6H, s), 1.10 (3H, s), 1.09 (3H, s) ppm.

LRMS (APCI): m / z [M + H] + 537.

Preparation 15: N-Benzyl-2- [3- (2 - {(2 R) -2- [6- (2,5-dimethylpyrrol-1-yl) -pyridin-3-yl] -2-hydroxy- ethylamino} -2-methyl-propyl) -phenyl] -acetamide i

° H Η H

30 h3c L Λ H, C CHg1 * J 'o 3 3 ch3 35 Prepared according to the method described for preparation 1 using the acid from preparation 34 and the suitable 1026329-

130 I

too amine to give the title compound as a pale yellow I

oil. I

1 H NMR (400 MHz, CD3 OD): δ * 8.58 (1H, s), 8.03-8.00 (1H, I

m), 7.31-7.10 (10 H, m), 5.82 (2 H, s), 4.82 (1 H, m, part I)

Shadowed by solvent), 4.35 (2 H, s), 3.54 l

(2H, s), 2.94-2.84 (2H, m), 2.77-2.66 (2H, dd), 2.04 (6H, I)

s), 1.07 (3 H, s), 1.04 (3 H, s) ppm. I

LRMS (electrospray): m / z [M + H] + 511, [M + Na] + 533, [M-H] "I

509. I

10 I

Preparation 16: 2- [3- (2 - {(2 R) -2- [6- (2,5-Dimethyl-pyrrol-1-)]

yl) -pyridin-3-yl] -2-hydroxy-ethylamino} -2-methyl-propyl) -1

phenyl] -N-phenethyl-acetamide I

I

° H Η I

-O I

20 c <1

CH3 I

Prepared according to the method described for preparation I

1 using the acid from preparation 34 and the suitable l

Too amine to give the title compound as a pale yellow I

oil. I

* H NMR (400 MHz, CD3 OD): δ * 8.58 (1H, s), 8.03-8.01 (1H, I

m), 7.24-7.09 (9H, m), 5.82 (2H, s), 4.85 (1H, m, part I)

shadowed by solvent), 3.45 (2H, s), 3.41-1

30.3, 38 (2H, m), 2.94-2.86 (2H, m), 2.78-2.66 (4H, m), 2.04 l

(6H, s), 1.08 (3H, s), 1.05 (3H, s) ppm. I

LRMS (electrospray): m / z [M + H] + 525, [M + Na] + 547, [Μ-Η] “I

523. I

1026329-I

5 131

Preparation 17: 2- [3- (2 - {(2 R) -2- [6- (2,5-Dimethyl-pyrrol-1-yl) -pyridin-3-yl] -2-hydroxyethylamino) -2 -methyl-propyl) -phenyl] -N- (3-phenyl-propyl) -acetamide

? H Η H

H.Q

I H 3 C CH 3 CH 3

Prepared by the method described for Preparation 1 using the acid from Preparation 34 and the suitable amine to give the title compound as a pale yellow oil.

X H NMR (400 MHz, CD3 OD): δ = 8.58 (lp, s), 8.02-8.00 (1H, m), 7.31-7.11 (10H, m), 5.82 ( 2 H, s), 4.82 (1 H, partially shaded by solvent), 3.49 (2 H, s), 3.20-20 3.17 (2 H, m), 2.94-2.85 (2 H , m), 2.79-2.67 (2H, m), 2.59-2.55 (2H, m), 2.04 (6H, s), 1.81-1.74 (2H, m) ), 1.08 (3 H, s), 1.05 (3 H, s) ppm.

LRMS (electrospray): m / z [M + H) + 539, [M + Na] + 561, [M-H] "537.

1026320 =

I 132 I

Preparation 18: N- (3,5-Dichlorobenzyl) -2- [3- (2 - {(2R) -2- [6- I

I (2,5-dimethyl-pyrrol-1-yl) -pyridin-3-yl] -2-hydroxy-ethyl-I

Amino} -2-methyl-propyl) -phenyl] -acetamide I

I 5 C! I

I oh H I

I X J · - H 3 C CH.T J o I

I // ^ N N 3 3 U I

I 10 I

CH3 i

I Prepared according to the method described for preparation I

I 1 using the acid from preparation 34 and the suitability I

I amine to give the title compound as a pale yellow I

I oil. I

1 X H NMR (400 MHz, CD 3 OD): δ = 8.59 (1 H, s), 8.03-8.01 (1 H, 1

M), 7.32-7.11 (8 H, m), 5.82 (2 H, s), 4.83 (1 H, m), part I

Slightly overshadowed by solvent), 4.32 (2 H, s), 3.56 I

20 (2H, s), 2.95-2.84 (2H, m), 2.79-2.67 (2H, dd), 2.04 (6H, 1)

S), 1.07 (3 H, s), 1.04 (3 H, s) ppm. I

I LRMS (electrospray): m / z [M + H] + 579/581, [M + Na] + 601/603, I

I [M-H] 577/579. I

1026329-I

133

Preparation 19: N- (3,4-Dimethyl-benzyl) -2- [3- (2 - {(2 R) -2- [6- (2,5-dimethyl-pyrrol-1-yl) -pyridin-3 -yl] -2-hydroxy-ethylamino} -2-methyl-propyl) -phenyl] -acetamide 5 ...

° H H

3L Λ J h3 ° ch3 II J o. Ch3 10 α n CH3

Prepared by the method described for Preparation 1 using the acid from Preparation 34 and the suitable amine to give the title compound as a pale yellow oil.

* H NMR (400 MHz, CD3 OD): δ = 8.61 (1 H, s), 8.05-8.03 (1 H, m), 7.32-6.95 (8 H, m), 5.83 (2H, s), 4.95-4.92 (1H, m), 4.36 (2H, s), 3.53 (2H, s), 3.05-3.03 (2H, m), 2.86-2.76 (2H, dd), 2.24 (3H, s), 2.13 (3H, s), 2.04 (6H, s), 1.15 (3H, s), 1.13 (3 H, s) ppm.

LRMS (electrospray): m / z [M + H] + 539, [M + Na] + 561, [M-H] "537.

1026329-

134. I

Preparation 20: N- (3,5-Dichlorobenzyl) -2- [3- (2 - {(2R) -2- [6- I

(2,5-dimethyl-pyrrol-1-yl) -pyridin-3-yl] -2-hydroxy-1

ethylamino) -2-methyl-propyl) -phenyl] -acetamide I

? H H H fX I

"X-V o

^ CH3 I

Prepared according to the method described for preparation I

1 using the acid from preparation 34 and the suitable l

15 amine to give the title compound as a pale yellow I

oil. I

* H NMR (400 MHz, CD3 OD): δ = 8.58 (1H, s), 8.03-8.01 (1H, I

m), 7.46-7.11 (8H, m), 5.82 (2H, s), 4.82 (1H, m, part I).

shadowed by solvent), 4.32 (2 H, s), 3.55 l

20 (2H, s), 2.94-2, 84 (2H, m), 2.78-2.66 (2H, dd), 2.04 (6H, I)

s), 1.06 (3 H, s), 1.03 (3 H, s) ppm. I

LRMS (electrospray): m / z [M + H] + 579/581, [M + Na] + 601/603, I

[M-H] 577/579. I

1026329-I

5 135

Preparation 21: [3 - ((2R) -2 - ((2R) -2- [6- (2,5-Dimethyl-pyrrol-1-yl) -pyridin-3-yl] -2-hydroxyethylamino} -propyl) -phenyl] -acetic acid

OH

h c Y ^ V ^ V ^ Y0H

3) ^ JL ^ ch, 1L J 10 CH 3

A solution of the ester from preparation 22 (5.45 g, 12.93 mmol) in tetrahydrofuran (80 ml) was treated with 15 1 N lithium hydroxide (26 ml, 26 mmol) and the resulting mixture was allowed to stir at room temperature for 16 hours. 1 N hydrochloric acid (26 ml, 26 mmol was added, and the solvent was removed in vacuo. The residue was azeotroped with toluene and then purified by flash column chromatography eluting with dichloromethane: methanol: 880 ammonia (90: 10: 1 changing) to 80: 20: 3 by volume) to give the title compound as a colorless solid (3.7 g). * 1 H NMR (400 MHz, DMSOd 6): δ - 8.54 (1H, bs), 7, 92-7.90 (1H, 25 m), 7.33 (1 H, d), 7.16 (1 H, d), 7.07.7, 00 (3 H, m), 5.77 (2 H, s) ), 4.77-4.74 (1 H, m), 3.47 (2 H, s), 2.91-2.75 (4 H, m), 2.43-2.38 (1 H, m), 2.01 (6H, s), 0.92 (3H, d) ppm.

LRMS (APCI): m / z [M + H] + 408.

1026329-1361 Preparation 22: [3 - ((2R) -2 - {(2R) -2- [6- (2,5-Dimethyl-pyrrol-1-yl) -pyridin-3-yl] - 2-hydroxy-ethylamino) -propyl) -phenyl] -acetic acid methyl ester

OH

CH3 I A solution of the epoxide from preparation 27 (5.43 g, 66% b / w crude material, 3.58 g, 16.7 mmol) and the amine I from Preparation 23 (4.15 g, 20.02 mmol) in dimethyl sulfoxide I (50 mL) was heated to 85 ° C under nitrogen for a period of 16 hours. The reaction mixture is cooled to room temperature and loaded directly onto a strong cation exchange column. The column was eluted with methanol (300 I 20 ml) and then the product was eluted with 2 M ammonia in methanol (100 ml). The solvent was removed in vacuo and the residue purified by flash column chromatography eluting with dichloromethane: methanol: 880 ammonia (100) changing to 98: 2: 0.2 by volume) to to give the title compound as a pale orange oil (5.45 g).

1 H NMR (400 MHz, CD 3 OD): δ - 8.54 (1 H, bs), 7.79 (1 H, dd), I 7.31-7.22 (2 H, m), 7.15-7 , 10 (3 H, m), 5.82 (2 H, s), 4.91-1.81 (1 H, m, partially overshadowed by solvent), I 3.34, 67 (3 H, s), 3.63 (2H, s), 3.04-2, 96 (1H, m), 2.88 (2H, I d), 2.81-2.74 (1H, m), 2.66-2.58 ( 1 H, m), 2.04 (6 H, s), I 1.09 (3 H, d) ppm.

LRMS (electrospray): m / z [M + H] + 422, [M + Na] + 444, [M-H] ~ I 420.

I 35 I 1026329-137

Preparation 23: [3 - ((2R) -2-Amino-propyl) -phenyl] -acetic acid methyl ester hydrochloride

CH 3 O

A solution of the amine from preparation 24 (7.69 g, 22 mmol) and ammonium formate (6.94 g, 110 mmol) was heated to 75 ° C in the presence of 20% palladium hydroxide-on-carbon (2, 00 g). After 90 minutes, the reaction mixture was cooled to room temperature, filtered through arbocel® 15 and the filtrate concentrated in vacuo. The residue was partitioned between dichloromethane (100 ml) and 880 ammonia (100 ml) and the organic phase separated. The aqueous phase was extracted with dichloromethane (100 ml) and the combined organic extracts dried (magnesium sulfate) and evaporated in vacuo to give the title compound as a colorless oil (4.78 g).

X H NMR (400 MHz, CD3 OD): δ = 7.27-7.23 (1 H, t), 7.13-7.09 (3 H, m), 3.67 (3 H, s), 3.63 ( 2 H, s), 3.12-3.05 (1 H, m), 2.67-2.57 (2 H, m), 1.06 (3 H, d) ppm.

LRMS (electrospray): m / z [M + H] + 208, [M + Na] + 230.

Preparation 24: {3 - [(2R) -2 - ((IR) -1-Phenyl-ethylamino) -propyl] -phenyl} -acetic acid methyl ester 30 n h öh 3 ch 3 o 35

A solution of the ketone from Preparation 25 (8.5 g, 41.2 mmol), (R) -α-methylbenzylamine (4.8 mL, 37.2 mmol); 1026329-

138 I

sodium triacetoxyborohydride (11.6 g, 56 inmol) and acetic acid

acid (2.2 ml, 38 mmol) in dichloromethane (400 ml) was 48 l

stirred at room temperature for 1 hour. The reaction mixture was I

quenched by the addition of saturated aqueous sodium bicarbonate

Carbonate (200 ml) and allowed to stir until bubbling

loved. The organic phase was separated and the aqueous I

phase extracted with dichloromethane (100 ml). The combined I

combined organic extracts were dried (magnesium I

sulphate) and evaporated in vacuo. Purification with be

Aid of flash column chromatography eluting with dichloromethane

thane: methanol: 880 ammonia (99: 1: 0.1 changing to I

95: 5: 0.5 by volume) gave a 4: 1 mixture of diasterees

omeren (R, R largest) as one as a pale yellow oil (8.71 I

g). Treatment with excess 1 M hydrogen chloride in methanol

15 thanol followed by three successive crystallizations I

(diisopropyl ether / methanol) gave the title compound as an I

colorless crystalline solid (5.68 g). I

X H NMR (400 MHz, CD 3 OD): δ = 7.52-7.48 (5H, m), 7.28-7.25

(1H, m), 7.18-7.16 (1H, m), 7.02-6.99 (2H, m), 4.59 (1H, I)

Q), 3.62 (2 H, s), 3.30 (3 H, s), 3.30-3.25 (1 H, m), 3.26 -1

3.15 (1 H, m), 2. 66-2, 60 (1 H, m), 1.68 (3 H, d), 1.18 (3 H, I)

d) ppm. I

LRMS (electrospray): m / z [M + H] + 312, [M + Na] + 334. I

Preparation 25: [3- (2-Oxo-propyl) -phenyl] -acetic acid methyl-1

ester I

O O I

A solution of the bromide from preparation 26 (15.0 l

35 g, 65.0 mmol), tributyltin methoxide (28.3 ml, 98 mmol), I

isopropenyl acetate (10.8 ml, 98.0 mmol), palladium (II) - I

acetate (750 mg, 3.30 mmol) and tri-ortho-tolylphosphine (2.0 l

1026329-I

139 g, 6.5 mmol) was stirred together in toluene (75 ml) at 100 ° C under nitrogen for 5 hours. After cooling, the reaction was diluted with ethyl acetate (150 ml) and 4 M aqueous potassium fluoride solution (90 ml) and stirred for 15 minutes. The mixture was filtered through arbocel® and the organic phase separated and evaporated in vacuo. The residue was purified by flash column chromatography silica gel eluting with a solvent gradient of diethyl ether: pentane: dichloromethane (0: 100: 0 changing to 25: 75: 0 then to 0: 0: 100, by volume) to title compound as a pale yellow oil (12.6 g).

X H NMR (400 MHz, CDCl 3): δ - 7.30 (1 H, t), 7.19 (1 H, d), 7.13-7.10 (2 H, m), 3.69 (5 H, s) , 3.61 (2 H, s), 2.15 (3 H, s) ppm.

LRMS (electrospray): m / z [M + NH 4] 4 224, [M + Na] + 229 .. Preparation 26: (3-Bromo-phenyl) -acetic acid methyl ester YYY ch3 Acetyl chloride (0.7 ml, 9 (3 mmol) was slowly added to a solution of (3-bromophenyl) acetic acid (20.0 g, 93 mmol) in methanol (500 mL) at 0 ° C under nitrogen and the reaction was allowed to warm gradually to room temperature for a period of 5 hours. The solvent was removed in vacuo and the residue dissolved in dichloromethane, dried (sodium sulfate) and concentrated in vacuo to give the title compound as a colorless oil (20.6 g).

X H NMR (400 MHz, CDCl 3): δ «7.37-7.45 (2H, m), 7.24-7.17 (2H, m), 3.70 (3H, s), 3.59 (2 H, s) ppm.

LRMS (electrospray):. m / z [M + Na] + 253.

1026329-140

Preparation 27: 2- (2,5-Dimethyl-pyrrol-1-yl) -5 - [(2 R) -oxira-I

Nylpyridine ch3 I 10 I A solution of the chloride from preparation 28 (12.0 g, 48.1 mmol) in tetrahydrofuran (20 ml) was slowly added to a solution of (-) - B-chlorodiisopino-camphenyl borane ( 20.2 g, 62.5 mmol) in tert-butyl methyl ether (15 ml) and tetrahydrofuran (30 ml) at -30 ° C under I nitrogen. The reaction was stirred at -30 ° C for 6 hours and then sodium perborate tetrahydrate (7.4 g, 48.1 l mmol) followed by tert-butyl methyl ether (50 ml) was added. The reaction was stirred at room temperature for 18 hours, treated with 2 M aqueous sodium hydroxide (190 ml) and stirred for a further 6 hours. The organic phase was separated and the aqueous phase was extracted with further tert-butyl methyl ether (50 ml). The combined organic extracts were washed with 1 M aqueous sodium hydroxide (50 ml), saturated aqueous sodium chloride (50 ml), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with pentane: dichloromethane (80: 2 changing to 100: 0, by volume) to give the crude epoxide (65% b / w , 11.0 g), which was used without further purification.

1 X H NMR (400 MHz, CDCl 3): δ = 8.58 (1H, bs), 7.68-7.66 (1H, 1dd), 7.22-7.20 (1H, d), 3, 97-3.96 (1 H, m), 3.26-3.24 (1 H, 35 m), 2.91-2.89 (1 H, m), 2.12 (6 H, s) ppm.

I LRMS (electrospray): m / z [M + N] + 215, [M + Na] + 237.

I 1026329-14

Preparation 28: 2-Chloro-1- [6- (2,5-dimethyl-pyrrol-1-yl) -pyridin-3-yl] -ethanone

5 O

H, C Τ ΓΊ. CH, 10.

A solution of 2.5 M n-butyl lithium in hexanes (35 ml, 87.6 mmol) was added to a solution of bromide from preparation 29 (20.0 g, 79.7 mmol) in tert-butyl methyl ether (300 ml) at -78 ° C under nitrogen for 10 minutes. The reaction was stirred for a further 10 minutes and 2-chloro-N-methoxy-N-methylacetamide (12.1 g, 87.6 mmol) in tert-butyl methyl ether (40 mL) was added slowly. The reaction was stirred for 20 minutes at -78 ° C and then 1 M hydrochloric acid (200 ml) was added. The mixture was allowed to warm to room temperature, stirred for 2 hours and the organic phase separated. The aqueous phase was extracted with tert-butyl methyl ether and the combined organic extracts were washed with water (100 ml), saturated aqueous sodium chloride (100 ml) and 1 M sodium hydroxide (100 ml). The organic phase was dried (sodium sulfate), concentrated in vacuo, and the residual oil purified by flash column chromatography on silica gel eluting with pentane: dichloromethane: methanol (75: 25: 0 changing to 0: 99: 1 by volume). The residue was recrystallized from pentane: dichloromethane to give the title compound as a yellow solid.

1 H NMR (400 MHz, CDCl 3): δ = 9.11 (1H, s), 8.34-8.33 (1H, 35 d), 7.32-7.30 (1 H, d), 5, 91 (2 H, s), 4.66 (2 H, s), 2.17 (6 H, s) ppm.

LRMS (electrospray): m / z [M-N] + 247.

1026329-I 142 I Preparation 29: 5-Bromo-2- (2, 5-dimethyl-pyrrol-1-yl) -pyridine yr I 10 ch3 2,5-Hexanedione (46.2 g, 0.41) mol) was added to a suspension of 2-amino-5-bromopyridine (50.0 g, 0.29 I mol) and the reaction heated to reflux for 24 hours under Dean and Stark conditions, para I Toluene sulfonic acid (100 mg) was added and the reaction I was refluxed for a further 18 hours.

8 ml of water was removed, so the reaction was cooled to room temperature, washed with water (100 ml) and passed through a plug of silica gel, eluting with toluene. The eluent was concentrated in vacuo and the residue dissolved in pentane: dichloromethane (1: 1 by volume) and passed through a plug of silica gel eluting with pentane: dichloromethane (1: 1 by volume). The eluent was concentrated in vacuo to give a red liquid which solidified on standing. The solid was recrystallized (isopropanol) to give the title compound as a pale yellow solid (54.4 g).

1 30 * H NMR (400 MHz, CDCl 3): δ * 8.66 (1 H, s), 7.93-7.92 (1 H, 1 d), 7.13-7.11 (1 H, d), 5.91 (2H, s), 2.13 (6H, s) ppm.

I LRMS (electrospray): m / z [M + N] + 252.

1026329-543

Preparation 30: [3- (2 - {(2 R) -2- [6- (2,5-Dimethylpyrrol-1-yl) pyridin-3-yl] -2-hydroxyethylamino} propyl) - phenyl] -acetic acid

OH

.ηλ fi T ΤΎ T

JVV CH »V * 0 10 Cl CH,

Prepared using the process for preparation 21 using the ester from preparation 31 to give the title compound as a colorless solid which was used without further purification.

* H NMR (400 MHz, DMSOd 6): S = 8.55 (1 H, s), 7.93 (1 H, t), 7.35 (1 H, d), 7.18-7.15 (1 H, m ), 7.10-7.03 (3 H, m), 5.77 (2 H, s), 4.87-4.80 (1 H, m), 3.48 (2 H, s), 3.01- 2.89 (4H, 20 m), 2.50-2.40 (1 H, m, partially overshadowed by solvent), 2.01 (6 H, s), 0.96 (3 H, d) ppm.

LRMS (electrospray): m / z [M + N] + 408.

Preparation 31: [3- (2 - {(2 R) -2- [6- (2,5-Dimethyl-pyrrol-1-yl) pyridin-3-yl] -2-hydroxyethylamino) propyl) -phenyl] -acetic acid methyl ester

OH

30 HaC CH 3 L ^ ch 3 o n ch 3

A solution of the amine from preparation 32 (2.0 g, 8.65 mmol), the ketone from preparation 25 (2.14 g, 10.0 35 1026329-144 I mmol), acetic acid (0.5 ml, 8.65 inmol) and sodium triacetoxyborohydride (2.75 g, 13.0 mmol) was stirred in dichloromethane (25 mL) for 18 hours at room temperature under nitrogen. The mixture was washed with water (25 ml) and the aqueous phase extracted with further dichloromethane (2 x 10 ml). The combined organic extracts were dried (magnesium sulfate), evaporated to dryness in vacuo and the residue purified by flash column chromatography on silica gel eluting with dichloromethane: methanol: 880 I 10 ammonia (98: 2: 0 changing to 95: 5: 0 then 95: 5: 0.5, by volume) to mix the title compound (1: 1).

Diastereoisomers) as a pale yellow oil (3.65 g).

1 H NMR (400 MHz, CDCl 3): δ 8.56 (1H, s), 7.87-7.84 (1H, 15m), 7.30-7.26 (1H, m, partial) overshadowed by solvent), 7.20-7.09 (4H, m), 5.88 (2H, s), 4.97-4.87 I (1H, m), 3.69 (3H, s), 3.62 (2H, s), 3.18-3, 03 (2H, m), 2.94-2.74 (3H, m), 2.10 (6H, s), 1.22 (3 H, d) ppm.

I LRMS (electrospray): m / z [M + N] + 422.

I 20

Preparation 32: (IR) -2-amino-1- [6- (2,5-dimethylpyrrol-1-yl) -pyridin-3-yl] -ethanol I / V / NH 2 b I CH * I A solution of the phthalimide from preparation 33 I (4.85 g, 13.4 mmol) in 8 M methylamine in ethanol (50 ml) I was stirred for 18 hours at room temperature under a nitrogen atmosphere. The reaction was concentrated under reduced pressure and the residue dissolved in methanol. This solution was passed through a strong cation exchange resin pattern eluting with methanol and then 2 N ammonia in methanol to elute the product. The eluent was concentrated in vacuo and the residue purified using. flash column chromatography on silica gel eluting with 5 dichloromethane: methanol: 880 ammonia (95: 5: 0 changing to 90: 10: 1, by volume) to give the title compound as a pale yellow solid (1.6 g).

1 H NMR (400 MHz, CDCl 3): δ 8.17 (1 H, s), 7.85 (1 H, d), 7.21 (1 H, d), 5.89 (2 H, s), 4.69 ( 1 H, t), 3.15-3.11 (1 H, 10 dd), 2.85-2.80 (1 H, dd), 2.11 (6 H, s) ppm.

LRMS (electrospray): m / z [M + N] + 232, [M + Na] + 254.

Preparation 33: 2 - {(2R) -2- [6- (2,5-Dimethyl-pyrrol-1-yl) -pyridin-3-yl] -2-hydroxy-ethyl} -isoindole-1,3-dione 15 O. / = \ 25

A solution of the crude epoxide from preparation 27 (30.0 g of 65% b / w epoxide, 19.50 g, 91.0 mmol), phthalimide (12.51 g, 85.0 mmol) and potassium phthalimide (2.78 g, 15.0 mmol) in N, N-dimethylformamide (200 mL) was heated to 90 ° C under nitrogen for 6 hours. After cooling, the reaction was stirred for 18 hours at room temperature, concentrated in vacuo and the residue partitioned between dichloromethane (600 ml) and water (400 ml). The organic phase was separated and the aqueous phase extracted with further dichloromethane (200 ml). The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Crystallization from ethyl acetate (300 ml) gave the title compound as a pale yellow crystalline solid (22.1 I * H NMR (400 MHz, DMSOde): δ = 8.42 (1H, s ), 7.90 (1 H, d), 7.80 (4 H, d), 7.30 (1 H, d), 5.90 (1 H, s), 5.80 (2 H, s), 5 5 .00 (1H, brs), 3.82 (1H, m), 3.75 (1H, n), 1.95 (6H, s) dprti.

I LRMS (electrospray): m / z [M + N] + 362.

Preparation 34: [3- (2 - {(2R) -2- [6- (2,5-Dimethyl-pyrrol-1-yl) -1-pyridin-3-yl) -2-hydroxyethylamino} - 2-methyl-propyl) -phenyl] -acetic acid

OH

I! L Λ j Hsc ChJ ^ J o I ^ 0Η3 20

Prepared according to the method described for preparation 21 using the ester from preparation 35 to give the title compound as a colorless solid.

1 X H NMR (400 MHz, CD3 OD): δ - 8.66 (1 H, s), 8.13-8.10 (1 H, I 25 m), 7.39 (1 H, d), 7.31-7 , 23 (3H, m), 7.14-7.12 (1H, m), I 5.83 (2H, s), 5.11-5.07 (1H, m), 3.55 (2H, s), 3.42-3.23 I (2H, m), 3.04-2.97 (2H, m), 2.05 (6H, s), 1.37 (3H, s), I 1 , 36 (3 H, s) ppm.

LRMS (electrospray): m / z [M + N] + 422, [M + Na] + 444, [M-N] 420 I.

I 1026329- 147

Preparation 35: [3- (2- {(2 R) -2- [6- (2,5-Dimethyl-pyrrol-1-yl) pyridin-3-yl] -2-hydroxyethylamino} -2-methyl -propyl) -phenyl] -acetic acid ethyl ester

5 OH

n3c (I jf X T Ί π

L A ^ H3c ch3 |

·. K.

Prepared according to the method described for preparation 22 using the epoxide from preparation 27 and the amine from preparation 45 to give the title compound as a pale yellow oil.

* H NMR (400 MHz, CD3 OD): δ - 8.58 (1 H, s), 8.04-8.01 (1 H, m), 7.32 (1 H, d), 7.24 (1 H, t ), 7.17-7.11 (3H, m), 5.82 (2H, s), 4.13 (2H, s), 3.62 (2H, s), 2.95-2.85 ( 2 H, m), 2.80-2.67 (2 H, dd), 2.04 (6 H, s), 1.22 (3 H, t), 1.09 (3 H, s), 1.06 (3 H, s) ppm.

LRMS (electrospray): m / z [M + N] + 450, [M + Na] + 472, [M-N] - 448.

1026329 = I 148 I Preparation 36: [4- (2 - {(2 R) -2- [6- (2,5-Dimethyl-pyrrol-1-yl) -1-pyridin-3-yl] -2-hydroxy- ethylamino} -2-methyl-propyl) -phenyl] -acetic acid

° H H

Prepared according to the method described for preparation 21 using the ester from preparation 37 to give the title compound as a pale yellow solid.

1 NMR (400 MHz, DMSOd 6): δ = 8.56 (1 H, s), 7.93 (1 H, d), I 7.32 (1 H, d), 7.1-7.06 (4 H, m ), 5.77 (2 H, s), 4.72 (1 H, 1 m), 3.46 (2 H, s), 2.83-2.82 (2 H, m), 2.60 (2 H, s) ), 2.01 (6 H, s), 0.95 (3 H, s), 0.93 (3 H, s) ppm.

LRMS (electrospray): m / z [M + N] + 422, [M-H] "420.

Preparation 37: [4- (2 - {(2 R) -2- [6- (2,5-Dimethylpyrrol-1-yl) pyridin-3-yl] -2-hydroxyethylamino} -2 -methyl-propyl) -phenyl] -acetic acid methyl ester 25.

H OH

Prepared according to the method described for preparation I 35 22 using the epoxide from preparation 27 and the amine from preparation I hs9 ίν-ΝΧΊΓΊff l 1 J h, c ch, JL Jl I 30 I ^ I ^ ch3 38 to give the title compound as an pale yellow oil.

1026329-149 * H NMR (400 MHz, CDCl 3): δ - 8.58 (1H, s), 7.82 (1H, d), 7.20 (3H, m), 7.15 (2H, m) ), 5.80 (2 H, s), 4.70 (1 H, m), 4.17 (2 H, s), 3.59 (2 H, s), 3.05 (1 H, m), 2.75 -2.65 (3 H, m), 2.10 (6 H, s), 1.25 (3 H, s), 1.18 (3 H, s), 1.17 (3 H, s) 5 ppm.

LRMS (electrospray): m / z [M + N] + 450, [M + Na] + 472, [M-H] ~ 448.

Preparation 38: [4- (2-Amino-2-methyl-propyl) -phenyl] -acetic acid ethyl ester, H.C. CH.I.

A solution of the ester from preparation 39 (1.99 g, 5.44 mmol) was treated with a solution of methylamine in ethanol (10 mL of 8 M solution, 80 mmol) and the resulting solution was allowed to stir at room temperature . After 3 hours, the solvent was removed in vacuo and the residue triturated with methanol to give N- [1,1-dimethyl-2- (4-methylcarbamoylmethyl-phenyl) -ethyl] -N'-methyl-phthalimide 25 as a colorless solid. The solid was treated with hydrochloric acid (100 ml of 6 N solution) and heated to 100 ° C for 48 hours. The solvent was removed in vacuo and the crude amino acid residue treated with a mixture of ethanol (50 ml) and concentrated sulfuric acid (2 ml) at room temperature for 16 hours. The solvent was removed in vacuo and the residue partitioned between dichloromethane (100 ml) and saturated aqueous potassium carbonate (100 ml). The organic phase was separated, dried (sodium sulfate) and the solvent removed in vacuo to give the title compound as a pale yellow oil (760 mg, 59%).

1026329-150 * H NMR (400 MHz, CDCl3): δ - 7.22 (2H, d), 7.15 (2H, d), I 4.17 (2H, q), 3.60 (2H, s), 2.61 (2H, s), 1.25 (3H, t), I 1.10 (6H, s) ppm.

I LRMS (electrospray): m / z [M + N] + 236.

Preparation 39: {4- [2- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -1,2-methyl-propyl-3-phenyl} -acetic acid ethyl ester I " A solution of the boronic acid ester from preparation 40 (3.32 g, 8.19 mmol) in tetrahydrofuran (35 ml) was treated with ethyl bromoacetate (0.75 ml, 6.8 mmol), palladium-I (II) acetate (46 mg, 0.20 mmol), tri-ortho-tolyl phosphine I (187 mg, 0.61 mmol), and potassium phosphate (7.24 g, 34 mmol) and I the resulting suspension for 16 hours at room temperature stirred under a nitrogen atmosphere. The reaction mixture was diluted with dichloromethane (150 ml), washed with water (100 ml, saturated aqueous sodium chloride (100 ml), dried (sodium sulfate) and evaporated in vacuo to give the title compound as an orange oil (1, 85 g, 74%).

X H NMR (400 MHz, CDCl 3): δ = 7.77 (2 H, m), 7.70 (2 H, m), 7.12 (2 H, d), 7.06 (2 H, d), 4, 12 (2H, q), 3.54 (2H, s), 3.26 (2H, s), 1.75 (6H, s), 1.23 (3H, t) ppm.

LRMS (electrospray): m / z [M + N] + 366, [M + Na] + 388.

1026329-15

Preparation 40: 2- (1,1-Dimethyl-2- [4- (4,4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) -phenyl] -ethyl) -isoindole-1 3-dione 0 ~ f0 YVvv H3C CH3 Ch3 »/ CH3 O2 / C3 H3

A solution of bromide from preparation 41 (6.88 g, 19 mmol), potassium acetate (5.65 g, 57 mmol), bis (pina colato) dibor (5.85 g, 23 mmol) and [1, 1'-bis (diphenylphosphino) ferrocene] palladium (II) chloride (0.80 g, 0 * 98 mmol) in dimethyl sulfoxide (100 mL) was heated to 80 ° C under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (300 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were washed with water (100 ml), saturated aqueous sodium chloride (100 ml), dried (sodium sulfate) and evaporated in vacuo. Purification by flash column chromatography on silica gel eluting with pentane: dichloromethane (60:40 changed to 0: 100, by volume) to give the title compound as a colorless oil (5.58 g, 72%).

1 H NMR (400 MHz, CDCl 3): δ 7.73 (2 H, m), 7.68 (2 H, m), 7.60 (2 H, d), 7.08 (2 H, d), 3.27 (2H, s), 1.74 (6H, s), 1.30 (12H, s) ppm.

1026329-I 152 I Preparation 41; 2- [2- (4-Bromo-phenyl) -1,1-dimethyl-ethyl] -1-isoindole-1,3-dione I 5 I 10 Br I A solution of the amine from preparation 42 (5.13 g, 22 mmol), carboethoxyphthalimide (5.91 g, 27 inmol) and 1 triethylamine (7.52 ml, 54 mmol) in toluene (80 ml) were heated to 110 ° C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and the solvent evaporated in vacuo. The residue was partitioned between dichloromethane (100 ml) and saturated sodium bicarbonate (100 ml). The organic phase was separated, dried (sodium sulfate) and evaporated in vacuo. Purification by flash column chromatography I on silica gel eluting with pentane: dichloromethane (60:40 I changing to 0: 100, by volume) gave the title compound as a colorless oil (5.14 g, 64%).

I 25 * H NMR (400 MHz, CDCl 3): δ - 7.78 (2H, m), 7.65 (2H, m), I 7.25 (2H, d), 6.98 (2H, d) , 3.20 (2H, s), 1.75 (6H, s) 1 ppm.

LRMS (electrospray): m / z [M + N] + 359, [M + NH <] + 376.

I, 1026329, 153

Preparation 42; 2- (4-Bromo-phenyl) -1,1-dimethyl-ethylamine

V

5 H 2 N

H, C CH.

A solution of the amide from Preparation 43 (19.0 g, 62 mmol), thiourea (5.70 g, 75 mmol) and acetic acid (30 mL) in ethanol (150 mL) was heated under a nitrogen atmosphere for 16 hours to reflux. The reaction mixture was cooled to room temperature and. filtered, the solid precipitate being washed with ethanol (50 ml). The filtrate was evaporated to dryness in vacuo and the residue partitioned between dichloromethane (500 ml) and 1 M aqueous sodium hydroxide (300 ml). The organic phase was separated and the aqueous extracted with dichloromethane (500 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (200 ml), dried (sodium sulfate) and the solvent removed in vacuo to give the title compound as a dark orange oil (12.58 g, 88%).

X H NMR (400 MHz, CDCl 3): δ = 7.41 (2 H, d), 7.05 (2 H, d), 2.60 (2 H, s), 1.08 (6 H, s) ppm.

LRMS (electrospray): m / z [M + N] + 228/230.

1026329-154 I Preparation 43: N- [2- (4-Bromo-phenyl) -1,1-dimethyl] -2-chloro-acetamide

I H

2-Chloroacetonitrile (8.8 ml, 140 mmol) was added to a solution of the alcohol from preparation 44 I (16.0 g, 70 mmol), in acetic acid (33 ml). The resulting solution was cooled to 0 ° C and treated with concentrated sulfuric acid (33 ml) while maintaining an internal temperature <10 ° C. The reaction mixture was then allowed to gradually warm to room temperature.

After 4 hours the reaction mixture was poured on ice and made basic with solid sodium carbonate. The solution was extracted with ethyl acetate (2 x 500 ml) and the combined organic extracts dried (sodium sulfate) and evaporated in vacuo to give the title compound as I a colorless solid (19.0 g, 89%) ).

1 H NMR (400 MHz, CDCl 3): δ = 7.41 (2 H, d), 7.00 (2 H, d), I 6.18 (1 H, s), 3.95 (2 H, s), 3.02 (2H, s), 1.35 (6H, s) 25 ppm.

I LRMS (electrospray): m / z [M + N] + 304/306.

Preparation 44: 1- (4-Bromo-phenyl) -2-methyl-propan-2-ol 30 HO> nn

Br 35

A solution of 4-bromophenylacetone (6.85 g, 32 l

mmol) in diethyl ether (100 ml) was cooled to 0 ° C and I

1026329- 155 treated with methyl magnesium bromide (23.5 ml of a 3 M solution in diethyl ether (70 iranol). The reaction mixture was allowed to warm gradually to room temperature. After 2 hours, the reaction was quenched by the addition of saturated aqueous ammonium chloride (200 ml). The organic phase was separated and washed with saturated sodium chloride (100 ml), dried (sodium sulfate) and evaporated in vacuo Purification by flash column chromatography on silica gel eluting with pentane: dichloro-methane (60%) 40 changing to 0: 100 by volume) gave the title compound as a colorless oil (6.23 g, 84%).

* H NMR (400 MHz, CDCl3): δ = 7.42 (2 H, d), 7.10 (2 H, d), 2.70 (2 H, s), 1.22 (6 H, s) ppm.

Preparation ^ 45: [3- (2-Amino-2-methyl-propyl) -phenyl] -acetic acid ethyl ester 20 h3c ^ o ^^^, nhj

O KJ

A solution of the amide from preparation 46 (5.1 g, 18 mmol), thiourea (1.6 g, 21 mmol) and acetic acid (18 mL) in ethanol (80 mL) was heated to boiling under a nitrogen atmosphere for 16 hours under reflux. The reaction mixture was cooled and filtered. The filtrate was evaporated to dryness in vacuo, the residue dissolved in ethanol (150 ml), saturated with hydrogen chloride gas, and the resulting solution heated to reflux for 16 hours. The solvent was evaporated to dryness in vacuo and the residue partitioned between ethyl acetate (200 ml) and 5% aqueous sodium carbonate (200 ml). The organic extract was washed with saturated sodium chloride (100 ml), dried (sodium sulfate) and evaporated in vacuo. The residue was purified using strong catalyst

Interchangeable resin, eluting with methanol and then 2 N

I ammonia in methanol to elute the product. The eluent I was concentrated in vacuo to give the title compound I as a yellow oil (2.68 g, 63%).

1 * 5 H NMR (400 MHz, CDCl 3): δ = 7.29-7.04 (4H, m), 4.08 (2H, Iq), 3.64 (2H, s), 2.57 (2H, s), 1.18 (3H, t), 0.99 '(6'H, s) 1 ppm.

LRMS (electrospray): m / z [M + N] + 236, [M + NH <] + 258.

Preparation 46: {3- [2- (2-Chloro-acetylamino) -2-methyl-propyl] -phenyl} -acetic acid I is H0YTr ^ Vci

10 H 3 C CH 3 O

Prepared using the process for preparation 43 using the alcohol from preparation 47 as starting material to give the title compound as a colorless solid.

1 H NMR (400 MHz, CDCl 3): δ = 7.31-7.06 (4 H, m), 6.19 (1 H, 1 bs), 3.95 (2 H, s), 3.62 (2 H, s), 3.02 (2 H, s), 1.36 (6 H, I 25 s) ppm.

I LRMS (electrospray): m / z [M-N] "282/284.

1026329-157.

Preparation 47: [3- (2-Hydroxy-2-methyl-propyl) -phenyl] -acetic acid O H 3 Cl 2 Prepared according to the method of preparation 44 using (3-ethoxycarbonylmethylphenyl) acetic acid as a starting material for the title compound to give as a pale yellow oil.

X H NMR (400 MHz, CDCl 3): δ = 7.30-7.12 (4H, m), 3.63 (2H, .15 s), 2.75 (2H, s), 1.22 (6H, s) ppm.

LRMS (electrospray): m / z [M + N] + 209.

Preparation 48: 2- [3 - - (2- {(2 R) -2- [6- (2,5-Dimethylpyrrol-1-yl) pyridin-3-yl] -2-hydroxyethylamino} -2-methylpropyl) ) -20 phenyl] -N- (4f-hydroxybiphenyl-3-ylmethyl) acetamide

° H Η H

Prepared according to the method described for preparation 1 using the acid from preparation 34 and the amine from preparation 73 to give the title compound as a brown-colored oil.

X H NMR (400 MHz, CD3 OD): δ = 8.54 (1 H, d), 7.97 (1 H, d), 7.35-7.38 (2 H, m), 7.27-7.32 (2H, m), 7.24-7.25 (2H, m), 7.17-7.22 (3H, m), 7.08-7.12 (2H, m), 6.78-6 , 80 (2 H, m), 5.81 (2 H, s), 4.78 (1 H, dd), 4.40 (2 H, s), 3.55 (2 H, s), 1026329-

158

I 2.80-2.90 (2H, m), 2.60 (2H, dd), 2.03 (6H, s), 1.03 (3H, I)

S), 1.00 (3 H, s) ppm. I

I LRMS (electrospray): m / z [M + N) + 603, [M + Na] + 625. I

Preparation 49: 2- [3- (2 - {(2 R) -2- [6- (2,5-Dimethylpyrrol-1-)]

1-yl) pyridin-3-yl] -2-hydroxy-ethylamino} -2-methyl-propyl) -1

Phenyl] -N- (4 * -hydroxybiphenyl-4-ylmethyl) acetamide I

I io I

I oh h hI

h n.

I Prepared according to the method described for preparation I

I 20 1 using the acid from preparation 34 and the amine I

I from preparation 82 to give the title compound as an I

I brown colored oil. I

1 X H NMR (400 MHz, CD 3 OD): δ 8.56 (1H, d), 7.98 (1H, dd), I

I 7.39-7.47 (4H, m), 7.23-7.31 (4H, m), 7.18-7.19 (2H, m),. I

I 25 7.11-7.13 (1H, m), 6.81-6.84 (2H, m), 5.82 (2H, s), 4.80 I

I (1H, dd), 4.88 (2H, s), 3.65 (2H, s), 2.83-2, 95 (2H, m), I

I 2.66 (2H, dd), 2.03 (6H, s), 1.06 (3H, s), 1.03 (3H, s) I

I ppm. I

I LRMS (electrospray): m / z [M + N] + 603, [M + Na] + 625. I

I 30 I

I 1026329-

Preparation 50: 2- [3 - ((2R) -2 - {(2R) -2- [6- (2,5-Dimethylpyrrol-1-yl) pyridin-3-yl] -2-hydroxyethylamino) propyl) - phenyl) -N- (4f-hydroxybiphenyl-3-ylmethyl) acetamide 159 5H H h 15 Prepared according to the method described for preparation 1 using the acid from preparation 21 and the amine from preparation 73 to give the title compound as a brown colored oil.

X H NMR (400 MHz, CD3 OD): δ = 8.49 (1 H, d), 7.90 (1 H, dd), 7.38-7.40 (1 H, m 7.31-7.35 (3 H , m), 7.22-7.29 (3H, m), 7.17-7.19 (2H, m), 7.06-7.13 (2H, m), 6.80-6.82 (2H, m), 5.81 (2H, s), 4.78 (1H, dd), 4.40 (2H, s), 3.55 (2H, s), 2.92 (1H, dd) , 2.81-2.83 (2 H, m), 2.70 (1 H, dd), 2.52-2.57 (1 H, m), 2.02 (6 H, s), 1.02 (3 H , s) ppm.

LRMS (electrospray): m / z {M + N] + 589, [M + Na] + 611.

1026329-1601 Preparation 51: 2-Γ3 - ((2R) -2 - {(2R) -2- [6- (2,5-Dimethylpyrrol-1-yl) pyridin-3-yl] -2-hydroxyethylamino ) propyl) phenyl] -N- (4-hydroxynaphthalen-1-yl-ethyl) -acetamide I-I Prepared according to the method described for preparation I 1 using the acid from preparation 21 and the amine I from preparation 79 to give the title compound to give as an I light brown foam.

1 X H NMR (400 MHz, CD 3 OD): δ = 8.47 (1 H, d), 8.20-8.23 (1 H, 1 20 m), 7.91 (1 H, dd), 7.84-7 , 86 (1H, m), 7.05-7.12 <2H, m), I 6.71 (1H, d), 5.81 (2H, s), 4.79 (1H, dd), 4 70 (2H, s), 2.68-2.91 (6H, m), 2.02 6h s), 1.01 (3H, d) ppm.

LRMS (electrospray): m / z [M + N] + 563, [M + Na] + 585.

1026329-5

Preparation 52: 3- (2 - {(2 R) -2- [6- (2,5-Dimethylpyrrol-1-yl) pyridin-3-yl] -2-hydroxyethylamino} -2-methylpropyl) -N- ( 4 '- hydroxybiphenyl-3-ylmethyl) benzamide 161

° H Η II I T

<X

Prepared according to the method described for preparation 1 using the acid from preparation 60 and the amine from preparation 73 to give the title compound as a colorless solid.

1 H NMR (400 MHz, CD 3 OD): δ = 8.59 (1H, d), 8.00 (1H, dd), 7.77-7.80 (2H, m), 7.53-7, 56 (1 H, m), 7.40-7.45 (5 H, m), 7.33 (1 H, t), 7.24-7.28 (2 H, m), 6.80-6.84 ( 2H, m), 5.82 (2H, s), 4.95 (1H, t), 4.58 (2H, dd), 3.12 (2H, d), 2.89 (2H, dd), 2.02 (6H, s), 1.2 (3H, s), 1.19 (3H, s) ppm.

LRMS (electrospray): m / z [M + N] + 589, [M + Na) + 611.

25 1026329 =

162 I

Preparation 53: 3- (2 - {(2 R) -2- [6- (2,5-Dlmethylpyrrol-1-yl) -1)

pyridin-3-yl] -2-hydroxy-ethylamino) -2-methylpropyl) -N- [2- I

(4-hydroxyphenyl) -2-methylpropyl] benzamide I

5 I

0H Hff

Prepared according to the method described for preparation I

1 using the acid from preparation 60 and the amine I

from preparation 76 to give the title compound as an I

light brown foam. I

NMR (400 MHz, CD3 OD): δ = 8.65 (1H, d), 8.10 (1H, dd), I

20 7.57-7.61 (2H, m), 7.38-7-7, 44 (3H, m), 7.24-7.28 (2H, m), I

6.72-6.76 (2 H, m), 5.83 (2 H, s), 5.03 (1 H, dd), 3.52 (2 H, I)

s), 3.22-3.28 (2H, m), 3.02 (2H, s), 2.05 (6H, s), 1.84 l

(6 H, s), 1.28 (3 H, s), 1.31 (3 H, s) ppm. I

LRMS (electrospray): m / z [M + N] + 555, [M + Na] + 577. I

25 I

1026329-I

Preparation 54: 3- (2 - {(2 R) -2- [6- (2,5-Dimethyl-pyrrol-1-yl) -1'-pyridin-3-yl] -2-hydroxyethyl-amino} -2-methylpropyl ) - N - [2- (4-hydroxy-2, 5-dimethylphenyl) ethyl] benzamide 163

OH

0H H 0 || Prepared according to the method described for Preparation 1 using the acid from Preparation 60 and the amine from Preparation 86 to give the title compound as a colorless solid.

1 H NMR (400 MHz, CD3 OD): δ = 8.59 (1H, d), 8.62 (1H, dd), 7.65-7.68 (2H, m), 7.38-7, 40 (2 H, m), 7.32 (1 H, d), 6.84 (1 H, s), 6.54 (1 H, s), 5.81 (2 H, S), 3.45 (2 H, s) ), 3.45 (2H, dt), 2.96 (1H, dd), 2.88-2.91 (2H, m), 2.73-2.81 (3H, m), 2.23 ( 3 H, s), 2.08 (3 H, s), 2.03 (3 H, s), 1.12 (3 H, s), 1.06 (3 H, s) ppm.

LRMS (electrospray): m / z [M + N] + 555, [M + Na] + 577.

1026329-

164 I

Preparation 55: 3- (2 - {(2 R) -2- [6- (2,5-Dimethylpyrrol-1-yl) -1)

pyridin-3-yl] -2-hydroxy-ethylamino) -2-methylpropyl) -N- [2- I

(4-hydroxy-2, 3-dimethylphenyl) ethyl] benzamide I

5 I

OH h O

10 v N -

Prepared according to the method described for preparation I

1 using the acid from preparation 60 and the amine I

from preparation 87 to give the title compound as an I

straw-colored foam. I

* H NMR (400 MHz, CD3 OD): 6 - 1.06 (3H, s), 1.13 (3H, s), 1

2.04 (6H, sj, 2.11 (3H, s), 2.24 (3H, s), 2.73 (1H, d), I

2.83-2.92 (4H, m), 2.97-3.02 (1H, m), 3.46-3.49 (2H, m), I

4.84 ((1H, m, partially overshadowed by solvent I

peak), 2.82 (2 H, s), 6.53 (1 H, d), 6.80 (1 H, d), 7.82 (1 H, I)

d), 7.38-7.41 (2 H, m), 7.65-7, 68 (2 H, m), 8.03 (1 H, dd), I

25 8.59 (1 H, s) ppm. I

LRMS (electrospray): m / z [M + N] + 555. I

1026329-I

Preparation 56: 3- (2 - {(2 R) -2- [6- (2,5-Dimethylpyrrol-1-yl) pyridin-3-yl] -2-hydroxyethylamino} -2-methylpropyl) -N - [2- (4-hydroxy-3-methylphenyl) ethyl] benzamide 5 165 Bere Prepared according to the method described for preparation 1 using the acid from preparation 60 and the amine from preparation 86 to give the title compound as a beige foam.

1 H NMR (400 MHz, CD3 OD): δ = 1.04 (3 H, s), 1.12 (3 H, s), 2.12 (9 H, s), 2.62 (1 H, d), 2, 73-2.87 (4H, m), 2.95 (1H, d), 3.52-3, 58 (1H, m), 3.74-3.81 (1H, m), 4.64 ( 1 H, d), 5.89 (2 H, s), 6.48 (1 H, bs), 6.63 (1 H, d), 6.86 (1 H, d), 6.95 (1 H, s), 7.20 l, h, d), 7.33 (1 H, t), 7.48 (1 H, s), 7.60 (1 H, d), 7.81 (1 H, d), 8.53 ( 1 H, s) ppm.

LRMS (electrospray): m / z [M + N] + 541, [M + Na] + 539.

1026329 I 166 I Preparation 57: 3 - ((2R) -2- {(2R) -2- [6- (2,5-Dimethylpyrrol-1-yl) pyridin-3-yl] -2-hydroxyethylamino} propyl) -N- [2- (4-hydroxy-2,5-dimethylphenyl) ethyl] benzamide I 5

I 0H

Prepared according to the method described for preparation I 1 using the acid from preparation 60 and the amine I from preparation 86 to give the title compound as a colorless solid.

1 X H NMR (400 MHz, CD 3 OD): δ = 8.53 (1 H, d), 7.96 (1 H, dd), 1 20 7.87-7.88 (2 H, m), 7.60-7 63 (2H, m), 7.29 (1H, d), 6.85 (1H, s), 6.54 (1H, s), 5.81 (2H, s), 4.84-4 85 (1H, m), 3.45 (2H, t), 3.02 (1H, dd), 2.86-2.92 (3H, m), 2.77-2.81 I (2H , m), 2,626-2.67 (1H, m), 2.23 (3H, s), 2.09 (3H, s), 2.03 (6H, s), 1.08 (3H, d) ) ppm.

LRMS (electrospray): m / z [M + N] + 541, [M + Na] + 563.

I 1026329-

Preparation 58: 3 - ((2R) -2 - {(2R) -2- [6- (2,5-Dlmethylpyrrol-1-yl) pyridin-3-yl] -2-hydroxyethylamino} propyl) -N- [ 2- (4-hydroxy-2,3-dimethylphenyl) ethyl] benzamide 167 5-10 v Nu 15 Prepared according to the method described for Preparation 1 using the acid from Preparation 68 and the amine from Preparation 87 to produce the title compound give as a straw-colored foam.

X H NMR (400 MHz, CD3 OD): δ = 1.09 (3 H, s), 1.10 (3 H, s), 2.03 (6 H, s), 2.12 (3 H, s), 2, 25 (3H, s), 2.62 (1H, dd), 2.83-2, 94 (5H, m), 3, 02-3.07 (1H, m), 3.45-3.48 ( 2 H, m), 4.85 (1 H, m, partially overshadowed by solvent peak), 5.81 (2 H, s), 6.53 (1 H, d), 6.80 (1 H, d), 7, 29 (1H, d), 7.86-7.89 (2H, m), 7.60-7.64 (2H, m), 7.96 (1H, dd), 8.52 (1H, d) ) ppm.

LRMS (electrospray): m / z [M + N] + 541, [M + Na] + 563.

1026329-1161 Preparation 59: 3 - ((2R) -2 - {(2R) -2- [6- (2,5-Dimethylpyrrol-1-yl) pyridin-3-yl] -2-hydroxyethylamino} propyl) -N- [2- (4-hydroxy-3-methylphenyl) ethyl] benzamide

Is

I.OH

Prepared according to the method described for preparation I 1 using the acid from preparation 68 and the amine I from preparation 87 to give the title compound as a light beige foam.

1 H NMR (400 MHz, CD 3 OD): δ - 1.12 (3 H, d), 2.09 (6 H, s), I 2.20 (3 H, s), 2.67-2.73 ( 3 H, m), 2.79 (2 H, t), 2.94-3.02 (2 H, m), 3.59-3.70 (2 H, m), 4.59 (1 H, dd), 5.88 (1H, s), I 6.21 (1H, t), 6.67 (1H, d), 6.88 (1H, dd), 6.97 (1H, d), I 7.18 (1H, d), 7.28-7.36 (2H, m), 7.49-7.52 (2H, m), 7.80 (1H, dd), 7.48 (1H, d) ppm .

LRMS (electrospray): m / z [M + N] + 527, [M-H] 525.

1026329-569

Preparation 60: 3- (2 - {(2 R) -2- [6- (2,5-Dimethylpyrrol-1-yl) pyridin-3-yl] -2-hydroxyethylamino} -2-methylpropyl) benzoic acid

OH O

ίο

Prepared according to the method described for preparation 11 using preparation 61 to give the title compound as a cream-colored powder.

* H NMR (400 MHz, CD3 OD): δ = 8.67 (1 H, d), 8.13 (1 H, d), 7.94 (1 H, d), 7.87-7.92 (2 H, m ), 7.40-7.47 (3 H, m), 5.83 (2 H, s), 5.08 (1 H, dd), 3.43 (1 H, dd), 3.32 (1 H, dd) , 3.10 (2 H, d), 2.06 (6 H, s), 1.35 (6 H, s) ppm.

LRMS (electrospray): m / z [M + N] + 408, [M-H] - 406.

Preparation 61: 3- (2 - {(2 R) -2- [6- (2,5-Dimethylpyrrol-1-yl) pyridin-3-yl] -2-hydroxyethylamino) -2-methylpropyl) -benzoic acid methyl ester 25

OH O

30

Prepared according to the method described for preparation 22 using the amine from preparation 62 and the epoxide from preparation 27 to give the title compound as a brown oil.

1026329-1 170 I X H NMR (400 MHz, CD3 OD): δ «8.57 (1H, d), 7.86-7.93 (3H, 1m), 7.36-7.38 (2H, m ), 7.20 (1H, d), 5.98 (2H, s), 4.65 (1H, d), 3.91 (3H, s), 3.05 (1H, d), 2, 76 (2H, d), 2.67 l (1H, dd), 2.11 (6H, s), 1.11 (6H, s) ppm.

LRMS (electrospray): m / z [M + N] + 422.

Preparation 62: 3- (3-Amino-2-methylpropyl) benzoic acid methyl ester I

CH3 (I

I ch3 CH3 I 15

A solution of preparation 63 (1.6 g, 5.2 inmol) in I

I dichloromethane (160 ml) was treated with trifl at 0 ° C

Luoracetic acid (13.6 ml) and allowed to stand for 2 hours

I warm up to room temperature. The solvent was added under I

I vacuum removed and the product purified using I

I cation exchange chromatography (methanol followed by 2 I

1 M ammonia in methanol) to give the title compound as I

A brown oil (1.06 g). I

1 * H NMR (400 MHz, CDCl 3): δ = 7.90-7.88 (1H, m), 7.84 (1H, I

S), 7.36-7.35 (2 H, m), 3.90 (3 H, s), 2.71 (2 H, s), 1.67 I

I (2H, bs), 1.12 (6H, s). I

I LRMS (electrospray): m / z 208 [M + N] +. I

I 30 I

I 1026329-5 171

Preparation 63: 3- (2-tert-Butoxycarbonylamino-2-methylpropyl) benzoic acid methyl ester h3c h 9h3 § ch3 o ch3 ch3 10

A solution of preparation 64 · (7.0 g, 21 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloro palladium (II) (1.74 g, 2.1 mmol) and triethylamine (5.94 ml) 43 mmol) in methanol (250 ml) was heated to 100 ° C for 12 hours under 100 psi of carbon monoxide. The reaction mixture was filtered through arbocel and the filtrate concentrated in vacuo and purified by flash column chromatography on silica gel eluting with dichloromethane: pentane (50:50 by volume) and yielding the title compound as a yellow solid (3.76 g).

* H NMR (400 MHz, CDCl3): δ = * 7.92-7.90 (1H, m), 7.82 (1H, s), 7.35-7.34 (2H, m), 4, 24 (1 H, bs), 3.90 (3 H, s), 3.05 (2 H, s), 1.48 (9 H, s), 1.26 (6 H, s).

LRMS (electrospray): m / z 208 [M + N-BOC] 4.

1026329 I 172 I Preparation 64: [2- (3-Bromophenyl) -1,1-dimethylethyl] carbamic acid tert-butyl ester I 5 I VtVyBr ch 3 o ch 3 10 I Preparation 65 (5.0 g, 22 mmol) ) was treated with di-tert-butyl dicarbonate (5.26 g, 24 mmol) in dichloromethane I (50 ml) and stirred for 20 hours. The reaction mixture was washed with water (50 ml) and the combined organic layers dried (sodium sulfate) and the solvent removed in vacuo. The crude material was purified using

from a cation exchange column (methanol followed by 2 M

Ammonia in methanol) followed by purification by flash column chromatography on silica gel eluting with dichloromethane to give the title compound as a brown oil (7.23 g).

1 H NMR (400 MHz, CDCl 3): δ - 7.35 (1 H, d), 7.30 (1 H, s), 7.15-7.11 (1 H, t), 7.05 (1 H, d) ), 4.24 (1 H, bs), 2.97 (2 H, 25 s), 1.50 (9 H, s), 1.27 (6 H, s). LRMS (electrospray): m / z 350 [ M + NH 4] +.

I 1026329-: 173

Preparation 65: 2- (3-Bromophenyl) -1,1-dimethylethylamine CH3

A solution of preparation 66 (32.0 g, 105 mmol), thiourea (9.60 g, 126 mmol) and acetic acid (50 ml) in ethanol (250 ml) was heated to refluxing overnight. The reaction mixture was cooled to room temperature and filtered, the filtrate was concentrated in vacuo and basified using aqueous sodium hydroxide solution (1 M, 450 ml). The product was extracted with dichloromethane (2 x 500 ml) and the combined organic layers washed with brine (50 ml), dried (sodium sulfate) and the solvent removed in vacuo to give the title compound as a black oil (23 g).

* H NMR (400 MHz, CDCl 3): δ = 7.36-7.32 (2H, m), 7.16-7.08 (2H, m), 2.62 (2H, s), 1.84 <2 H, bs), 1.12 (6 H, s).

LRMS (electrospray): m / z 228 [M + H] +.

Preparation 66: N- [2- (3-Bromophenyl) -1,1-dimethylethyl] -2-chloroacetamide H PHg 30 c, R n'ttTy 0 CH 3

Chloroacetonitrile (6.63 ml, 105 mmol) was added to a stirred solution of preparation 67 (12.0 g, 52.0 mmol) in acetic acid (25 ml) at room temperature. The resulting solution was cooled to 0 ° C and concentrated 1026329-174 I sulfuric acid (25 ml) was added keeping the temperature <10 ° C. The resulting solution was allowed to stir for 1 hour and was then poured onto ice and made basic by the addition of solid potassium carbonate. The product was extracted with ethyl acetate (2 x 500 ml), the organic layers combined and washed with water (50 ml), dried (sodium sulfate) and the solvent removed in vacuo to give the title compound as an orange solid (16.08 g).

10 X H NMR (400 MHz, CDCl 3): δ * 7.39-7.32 (1 H, d), 7.26 (1 H, 1 s), 7.1-7.13 (1 H, t), 7 , 08-7.03 (1H, d), 6.17 (1H, bs), I 3.94 (2H, s), 3.02 (2H, s), 1.37 (6H, s).

I CHN for C 16 H 18 BrClNO calculated (found): C 47.32 (47.26)., H 4.96 (4.87), N 4.60 (4.65). »15 LRMS (electrospray): m / z 306 [M + H] +.

Preparation 67; 1- (3-Bromophenyl) -2-methylpropan-2-ol) 1 PH 3 - CH 1 Methyl magnesium bromide (3 M solution in diethyl ether, 51.6 ml, 155 mmol) was slowly added to an I solution of 1- (3-bromophenyl) propan-2-one (15.0 g, 70 l mmol) in dry diethyl ether (200 ml) at 0 ° C. The resulting mixture was allowed to stand for 3 hours, then cooled to 0 ° C and slowly quenched with saturated aqueous

I ammonium chloride solution. The organic phase was washed with brine, dried (sodium sulfate). The yellow oil I

was then purified by column chromatography

silica gel eluting with dichloromethane: pentane: I

35 methanol (90: 5: 5 by volume) and yielded a pale yellow

oil (13.26 g). I

1026329-175 * H NMR (400 MHz, CDCl 3): δ = 7.40 (2 H, m), 7.15 (2 H, m), 2.74 (2 H, s), 1.42 (1 H, bs) , 1.22 (6H, s) ..

Preparation 68: 3 - ((2R) -2 - {(2R) -2- [6- (2,5-Dimethylpyrrol-1-5-yl) pyridin-3-yl] -2-hydroxyethylamino) propyl) benzoic acid

° H II

10 Hg

Prepared according to the method described for preparation 21 using preparation 69 to give the title compound as an orange solid.

2 H NMR (400 MHz, CD3 OD): δ = 8.84 (1 H, d), 8.08 (1 H, dd), 7.87-7.89 (2 H, m), 7.37-7.40 ( 3 H, m), 5.82 (2 H, s), 5.11 (1 H, dd) 3.57-3.63 (1 H, m), 3.34-3.39 (2 H, m), 3 , 23-3.28 (1 H, m), 2.81 (1 H, dd), 2.05 (6 H, s), 1.26 (3 H, d) ppm.

LRMS (electrospray): m / z [M + H] + 394, [M-H] 392.

Preparation 69: 3 - ((2R) -2 - {(2R) -2- [6- (2,5-Dimethylpyrrol-1-yl) pyridin-3-yl] -2-hydroxyethylamino} propylbenzoic acid methyl ester

OH O

<< N 35

Prepared according to the method described for preparation 22 using the amine from preparation 70 and the epoxy from preparation 27 to give the title compound as a brown oil.

1 H NMR (400 MHz, CD3 OD): δ = 8.53 (1H, d), 7.95 (1H, dd), 7.84-7; 87 (2H, m), 7.45-7.48 (1H, m), 7.38-7.42 (1H, m), I 7.27 (1H, d), 5.81 (2H, s), 4.83-4.85 (1 H, m), 3.88 (3 H, 1 s), 2.99 (1 H, q), 2.86-2.91 (3 H, m), 2, 63 (1H, dd), 2.03 I (6H, s), 1.07 (3H, d) ppm.

LRMS (electrospray): m / z [M + H] + 408.

Preparation 70: Methyl {3 - [(2 R) -2-aminopropyl] phenyl) acetate

15 PH3 KjJ

A solution from preparation 72 (13.64 g, 40.9 in mol) I and ammonium formate (12.9 g, 204 mmol) in ethanol (200 ml) was heated to reflux in the presence of 20 % palladium hydroxide on carbon (Pd (OH) 2 / C, 1.36 g). After 3 hours, the reaction mixture was cooled to room temperature, filtered through arbocel and the filtrate concentrated in vacuo. The residue was partitioned between dichloromethane (200 ml) and 880 ammonia (100 ml) and the organic phase separated. The aqueous phase was extracted with further dichloromethane (3 x 100 ml) and the combined organic extracts washed with brine (100 ml), dried (sodium sulfate) and evaporated in vacuo to the title compound (8.48 g) as a pale I yellow oil.

1 H NMR (400 MHz, CDCl 3): δ * 7.90-7.87 (2H, m), 7.38-7.34 I (2H, m), 3.90 (3H, s), 3 , 26-3.17 (1H, m), 2.78-2.73 (1H, 1dd), 2.64-2.59 (1H, dd), 1.14-1.12 (3H, d) ) ppm.

35 LRMS (electrospray): m / z [M + H] + 194.

1026329- 177

Preparation 71: Methyl- [3 - ((2R) -2 - {[(IR) -1-phenyl-ethyl] -amino) -propyl) -phenyl] -acetate hydrochloride 5 C 6 h 6 ch 3 A solution of preparation 72 (45.3 g, 236 inmol), (R) -α-methylbenzylamine (27.6 ml, 214 mmol), sodium triacetoxyborohydride (68.1 g, 321 mmol) and acetic acid (14.7 ml, 257 mmol) in dichloromethane (1500 ml) was stirred for 18 hours at room temperature. The reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate (600 ml) and allowed to stir until bubbling ceased. The organic phase was separated and the aqueous phase extracted with further dichloromethane (2 x 100 ml). The combined organic extracts were washed with brine 20 (100 ml), dried (sodium sulfate), filtered through

Celite and evaporated in vacuo. The oil was dissolved in methanol (200 ml), treated with 1 M hydrogen chloride in methanol (300 ml) and evaporated in vacuo to give a 4: 1 mixture of diastereomers (R, R

25) as an off-white hydrochloride salt. Two consecutive crystallizations (diisopropyl ether / methanol) gave the title compound (27.3 g) as a colorless crystalline solid.

1 H NMR (400 MHz, CD 3 OD): δ 7.92-7.90 (1 H, d), 7.75 (1 H, 30 s), 7.55-7.49 (5 H, m), 7, 45-7.42 (1H, dd), 7.35-7.33 (1H, d), 4.68-4.63 (1H, q), 3.90 (3H, s), 3.43- 3.38 (1H, dd), 3.25-3.19 (1H, m), 2.71-2.65 (1H, dd), 1.71-1.69 (3H, d), 1, 17-1.16 (3 H, d) ppm.

1026329 I 178 I Preparation 72: Methyl [3- (2-oxopropyl) phenyl] acetate I 0 I 5 I O.

Tributyltin methoxide (80.3 ml, 279 mmol), methyl 3- bromobenzoate (53.5 g, 249 mmol), isopropenyl acetate (39.4 l mL, 3.58 mmol), palladium (II) acetate (2 (6 g, 11.6 mmol) and I tri-o-tolylphosphine (7.1 g, 23.2 mmol) were stirred in toluene (350 ml) for 18 hours under I nitrogen at 100 ° C.

After cooling, the reaction was treated with 4 M aqueous potassium fluoride solution (560 ml) and stirred for 2 hours. The resulting mixture was diluted with further toluene (200 ml) and filtered through Celite, the filter layer being washed with ethyl acetate. The organic phase was separated, dried (sodium sulfate) and evaporated in vacuo to dryness. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate rpentane (10:90, changing to 20:80, by volume) to give the title compound (45.3 g) as an oran - your oil).

25 a H NMR (400 MHz, CDCl 3): δ * 7.95-7.93 (1 H, D), 7.87 (1 H, IS), 7.43-7.37 (2 H, M), 3.91 (3 H, S), 3.75 (2 H, S), 2.18 (3 H, S) ppm.

LRMS (electrospray): m / z [M + Na] + 215, [M-H] "191.

1026329, 179

Preparation 73: 3 '- (Aminomethyl) biphenyl-4-ol 10

The phenol from preparation 74 (0.73 g, 2.43 mmol) was treated with 4 M HCl in dioxane (6 mL, 24.3 in mol) and the resulting solution was allowed to stir at room temperature for 3 hours. The solvent was removed in vacuo to give the title compound as a colorless solid.

1 H NMR (400 MHz, CD3 OD) δ: 7.65 (s, 1H), 7.61 (d, 1H), 7.45-7.50 (m, 3Hj, 7.34 (d, 1H), 6.87 (d, 2H), 4.17 (s, 2H) ppm.

MS (electrospray): m / z 198 [M-H] ", 200 [M + H] +.

20

Preparation 74: tert-Butyl [(4'-hydroxybiphenyl-3-yl) methyl] - carbamate 25 ^ phy • Η Π 30

A solution of the iodide from preparation 75 (0.75 g, 2.25 mmol), 4-hydroxyphenylboronic acid (0.62 g, 4.50 mmol), 1,1'-bis (diphenylphosphino) ferrocenyl palladium (II) - 35 chloride (0.11 g, 0> 14 mmol), in N, N-dimethylformamide (14 ml) was treated with 2 M aqueous sodium carbonate (4 ml). and the resulting mixture heated to 80 ° C for 16 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with ethyl acetate: pentane (1: 3) to give the title compound as a pale pink crystalline solid (0.73 g) ).

1 H NMR (400 MHz, CDCl 3) δ: 7.43-7.45 (m, 4H), 7.37 (dd, 1H), 7.21 (d, 1H), 6.89 (d, 2 H), 4.87-4.94 (bs, 1 H), 4.33-4.41 (m, 2 H), 1.47 (s, 9 H) ppm.

MS (electrospray): m / z 298 [M-H] ", 322 [M + Na] +.

I 10 I

I Preparation 75: tert-Butyl (3-iodobenzyl) carbamate I ^ X, I 15

A suspension of 3-iodobenzyl amine hydrochloride (4.95 g, 18.4 mmol) in dichloromethane (100 ml) was treated with triethylamine (3.1 ml, 22 mmol) and di-t-butyl dicarbonate ( 4.40 g, 20 mmol) and the resulting solution I was left under a nitrogen atmosphere at room temperature for 1.5 hours

Stirring by temperature. The reaction mixture was washed with 2 M

Hydrochloric acid (30 ml), water (30 ml), dried (sodium sulfate), and the solvent removed in vacuo to give the title compound as a colorless solid (6.43 g).

1 H NMR (400 MHz, CDCl 3) 5: 7.63 (s, 1H), 7.25 (d, 1H), 7.06 (dd, 1H), 4.79-7.89 (bs, 1H) ), 4.21-4.30 (m, 2H), 1.46 (s, 9H) ppm.

MS (electrospray): m / z 332 [M-H] +, 356 [M + Na] +.

1026329- 181

Preparation 76: [2- (4 - {[tert-Butyl (dimethyl) silyl] oxy} phenyl) -2-methylpropyl] amine TBDMSO4 ^ A solution of the nitrile. from preparation 77 (0.75 / 2.7 mmol) in diethyl ether (5 ml) was added dropwise to a cold (6 ° C) solution of lithium aluminum hydride in diethyl ether (2.98 ml of a 1 M solution). The resulting solution was stirred at 0 ° C for 3 hours and then quenched by adding water (0.1 ml), 2 N aqueous sodium chloride (0.1 ml), and further water (0.3 ml). The resulting suspension was filtered and the filtrate concentrated in vacuo. Purification by column chromatography on silica gel eluting. with dichloromethane: methanol: 0.880 ammonia (97: 3: 0.5 changing to 93: 7: 0.5) gave the title compound as a colorless oil (0.52 g).

X H NMR (400 MHz, CDCl 3) δ: 7.16 (d, 2H), 6.78 (d, 2H), 2.73 (s, 2H), 1.25 (s, 6H), 1.00 ( bs, 2H), 0.97 (s, 9H), 0.18 (s, 6H) ppm.

MS (APCI) m / z 280 [M + H] + 1026329-1 182 I Preparation 77: 2- (4 - {[tert-Butyl (dimethyl) silyl] oxy} phenyl) -1-2-methylpropanitrile TBDMSO ^^ I A solution of the nitrile from preparation 78 (5.62 I g, 22.7 in mol), methyl iodide (3.11 ml, 50 mmol), and 18-1 crown-6 (1.5 g, 5.6 mmol) ) in dry tetrahydrofuran (300 ml) was cooled to -78 ° C under a nitrogen atmosphere.

Potassium tert-butoxide (50 ml of a 1 M solution in te

Trahydrofuran, 50 ml) was added dropwise for 20 minutes

I nuts were added and the reaction mixture was then left 1

I gradually warm up to room temperature. After 2 hours I

I the reaction was again cooled to -78 ° C and quenched by I

Addition of saturated aqueous ammonium chloride (200 l

20 ml) and allowed to warm to room temperature. The re- I

I sulphating solution was extracted with ethyl acetate I

(300 ml x 2), the combined organics were I

dried (sodium sulfate) and the solvent in vacuum I

I deleted. Purification by column chromatography I

Over silica gel eluting with ethyl acetate: penate (0: 100

changing to 10:90) gave the title connection as an I

I colorless oil (4.75 g). I

1 * H NMR (400 MHz, CDCl 3) 6: 7.30 (d, 2H), 6.82 (d, 2H), 1.68 I (s, 6H), 0.97 (s, 9H), 0 , 19 (s, 6H) ppm.

I MS (APCI) m / z 293 [M + NH <] + I

I 1026329- 183

Preparation 78: (4 - {[tert-Butyl (dimethyl) silyl] oxy) phenyl) - acetonitrile

5 rj ^ V ^^ CN

TBDMSO 4 ^ A solution of (4-hydroxyphenyl) acetonitrile (6.01 g, 45.1 mmol) in N, N-dimethylformamide (60 ml) was treated with imidazole (3.81 g, 58.6 mmol), tert-butyl dimethylsilyl chloride (7.49 g, 49.6 mmol) and N, N-dimethylaminopyridine (20 mg) and the resulting solution was allowed to stir for 16 hours under a nitrogen atmosphere at room temperature. The reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (200 ml x 2). The combined organic extracts were washed with saturated aqueous sodium chloride (20.0 ml), dried (sodium sulfate) and the solvent was removed in vacuo. Purification by column chromatography on silica gel eluting with ethyl acetate: pentane (0: 100 changing to 10:90) gave the title compound as a pale yellow oil (9.44 g).

25 αΗ NMR (400 MHz, CDCl 3) δ: 7.17 (d, 2H), 6.82 (d, 2H), 3.66 (s, 2H), 0.97 (s, 9H), 0.19 '(s, 6H) ppm.

MS (APCI) m / z 265 [M + NH 4] + 1026329-1 184 I Preparation 79: [(4 - {[tert-Butyl (dimethyl) silyl] oxy) -1-naphth-1-yl) methyl] amine I 5 ^ NH 2 CO

I OTBDMS

Preparation 80 (250 mg, 0.76 mol) and dimethyl barbituric acid (581 mg, 3.72 mmol) were heated to reflux in dichloromethane (30 ml) for 15 minutes. Tetrakis (triphenylphosphinepalladium (O) (88 mg, 67 pmol) was added and the resulting mixture heated to reflux for 20 hours. The solvent was removed and the material dissolved in ethyl acetate (30 ml). I washed with sodium hydroxide (1 (M, 3 x 30 ml). The aqueous layer was extracted with ethyl acetate (30 ml). The combined organic layers were passed through a strong cation exchange resin column (methanol to 1 M ammo - niak in methanol) and yielded a brown oil (162 mg).

1 H NMR (400 MHz, CDCl 3) δ: 8.25 (d, 1H), 8.00 (d, 1H), I 7.46-7.55 (m, 4H>, 7.27 (t (1 H), 6.80 (d, 1 H), 4.24 (s, 1 2 H), 2.31 (bs, 2 H), 1.09 (s, 9 H), 0.28 (s, 6 H) ppm .

1026329- 185

Preparation 80: N - [(4 - {[tert-Butyl (dimethyl) silyl] oxy} -1-naphthyl) methyl] prop-2-en-1-amine 5

C ^ CH 2

οφ

10 OTBDMS

Preparation 81 (1.00 g, 3.5 inmol), allylamine (219 mg, 3.85 mmol) and acetic acid (2 drops) were dissolved in dichloromethane (10 ml) and stirred for 15 minutes * Sodium triace-15-boron borohydride (1, 11 g, 5.25 mmol) was added and the resulting mixture was allowed to stir for 4 days. Sodium hydrogen carbonate (10 ml) was added and the mixture was stirred for a further 90 minutes. The mixture was separated and the aqueous phase re-extracted with dichloromethane (10 ml) and the combined organic layers washed with brine (20 ml) and dried (MgSO 4). The material was purified by chromatography (0-10% methanol in dichloromethane + 1% ammonia), the material was further purified by chromatography (0-25% ethyl acetate in pentane) to give a dark yellow oil (250 mg).

* H NMR (400 MHz, CDCl 3) δ: 8.25 (d, 1H), 8.07 (d, 1H), 7.47-7.57 (m, 2H), 7.32 (d, 1H) , 6.82 (d, 1H), 5.95-6.05 (m, 1H), 5.25 (dd, 1H), 5.16 (dd, 1H), 4.17 (s, 2H), 3.39 (d, 2H), 1.97 (bs, 1H), 1.1 (s, 9H), 0.30 (s, 6H) ppm.

MS (electrospray): m / z 328 [M + H) +, 655 [2M + H] +.

1026329-1861 Preparation 81: 4 - {[tert-Butyl (dimethyl) silyl] oxy) -1-naphthaldehyde

I

I 5 f οφ

I OTBDMS

10 I 4-Hydroxynaphthalene-1-carbaldehyde (2.00 g, 11.63 I mmol), terb-butyldimethylsilyl chloride (1.93 g, 12.80 I mmol), imidazole (983 mg, 15.12 mmol) and N, N-dimethyl-aminopyridine (4 mg) in N, N-dimethylformamide (20 ml) were stirred for 20 hours at room temperature. The solvent I was removed and the mixture was suspended in ethyl acetate (20 ml) and washed with water (20 ml). The aqueous I phase was extracted with ethyl acetate (20 ml) and the combined organic layers washed with brine (2 x 20 I ml) and dried (MgSOO. The solvent was removed and the product was left as a brown oil they solidified after I.

1 * H NMR (400 MHz, CDCl 3) δ: 10.21 (s, 1H), 9.30 (dd, 1H), I 25 8.27 (dd, 1H), 7.86 (d, 1H), 7.68 (dd, 1H)> 7.56 (dd, 1H), 6.94 (d, 1H), 1.10 (s, 9H), 0.36 (s, 6H).

1 I

I 1026329- 187

Preparation 82: 4 '- (Aminomethyl) biphenyl-4-ol hydrochloride

A solution of 4'-hydroxybiphenyl-4-carbonitrile (10.0 g, 51.22 mmol) in tetrahydrofuran (500 ml) was treated with a solution of diborane (1 M in tetrahydrofuran, 102 ml, 102 mmol) and the resulting solution 6 heated under reflux for 15 hours under nitrogen. After cooling to room temperature, the mixture was treated with hydrochloric acid (6 N, 200 ml) and heated to reflux for 30 minutes. The solvents were removed and dissolved in methanol, then added on a strong cation exchange column (methanol then 1 M ammonia in methanol) and yielded a cream solid. The solid was taken up in 1 M hydrochloric acid in methanol and after removal of the solvent a yellow solid was obtained (3.8 g).

25 X H NMR (400 MHz, CD 3 OD) 5: 7 * 62 (d, 2H), 7.44-7.46 (m, 4H), 6.83 (d, 2H), 4.15 (s, 2H) ppm.

1026329 I 188 I Preparation 83: (4-Hydroxy-2,5-dimethylphenyl) acetonitrile 5 T * I / * x

CHa. I

A solution of (4-methoxy-2,5-dimethylphenyl) acetonitrile (0.5 g, 2.9 mmol) in dichloromethane (10 ml) was cooled to -80 ° C and treated with a solution of I boron tribromide in dichloromethane (14.3 ml of a 1 M solution, 14.3 mmol). The reaction mixture was stirred at -80 ° C for a further 30 minutes and then allowed to gradually warm to room temperature

I ran for 2 hours. The reaction mixture was added

I quench with saturated aqueous sodium bicarbonate (20 ml)

And the organic phase was separated. The organic fa

was washed with saturated aqueous sodium chloride I

I (20 ml), dried (sodium sulfate) and the solvent

I removed in vacuo to give a pale brown solid

. Purification by column chromatography on silica

Eluting 25 g of gel with ethyl acetate rpentane (1: 4 changing I

I to 1: 2) gave the title compound as a colorless solid I

I substance (0.28 g). I

1 * H NMR (400 MHz, CD3 OD) 5: 2.13 (s, 3H), 2.23 (s, 3H), 3.66 I (s, 2H), 6.60 (s, 1H), 6 98 (s, 1H) ppm.

MS (electrospray): m / z 160 [M-H] -. I

I 1026329- 189

Preparation 84: (4-Hydroxy-2,3-dimethylphenyl) acetonitrile

II

Prepared from (4-methoxy-2,3-dimethylphenyl) acetone using the method from Preparation 83 to give the title compound as a pale yellow solid.

* H NMR. (400 MHz, CDCl 3) δ: 2.20 (s, 3H), 2.24 (s, 3H), 3.62 (s, 2H), 4.91 (bs, 1H), 6.64 (d , 1 H), 7.03 (d, 1 H) ppm.

MS (electrospray): m / z 160 [M-H] ".

15

Preparation 85: (4-Hydroxy-3-methylphenyl) acetonitrile CH 3

20 ^ L ^ 0H

(| T

Prepared from (4-methoxy-3-methylphenyl) acetone using the method from Preparation 83 to give the title compound as a pale yellow solid.

* H NMR (400 MHz, CDCl3) δ: 2.25 (s, 3H), 3.65 (s, 2H), 4.98 (bs, 1H), 6.76 (d, 1H), 7.01 (d, 1 H), 7.07 (s, 1 H) ppm.

MS (electrospray): m / z 146 [M-H].

30 1028329-190

Preparation 86: 4- (2-Aminoethyl) -2,5-dimethylphenol I CH, 5 ^ 1 ^ oh I CH, I 10 I A solution of the nitrile from preparation 83 (0.28 g, 1.74 mmol) in ethanol (15 ml) was hydrogenated at 60 psi over Raney nickel (0.1 g, wt%) for 16 hours.

The reaction mixture was filtered and the solvent removed in vacuo. The residue was purified using strong cation exchange resin eluting non-basic impurities with methanol and then 1 M ammonia in methanol to give the title compound as a colorless oil.

1 20 * H NMR (400 MHz, CD 3 OD) δ: 2.11 (s, 3H), 2.19 (s, 3H), I 2.63-2.67 (m, 2H), 2.72-2 , 76 (m, 2H), 6.54 (s, 1H), 6.81 I (s, 1H) ppm.

MS (electrospray): m / z 166 [M + H] +.

Preparation 87: 4- (2-Aminoethyl) -2,3-dimethylphenol.

H, c. Js. .OH

Prepared from the nitrile of preparation 84 by the method of preparation 86 to give the title compound as a colorless oil.

1 H NMR (400 MHz, CD3 OD) 6: 2.12 (s, 3H), 2.19 (s, 3H), 1.68 - 2.75 (m, 4H), 6.55 (d, 1H) ), 6.78 (d, 1 H) ppm.

1026329- 191 MS (electrospray): m / z 166 [M + H] '1'.

Preparation 88: 4- (2-Aminoethyl) -2-methylphenol 5-10

Prepared from the nitrile of preparation 85 using the method of preparation 86 to give the title polymer compound as a colorless oil.

1 H NMR (400 MHz, CD3 OD) δ: 2.15 (s, 3H), 2.60-2.64 (m, 2H), 2.79-2.83 (m, 2H), 6.66 (d, 1 H), 6.82 (d, 1 H) 6.90 (s, 1 H) ppm.

MS (electrospray): m / z 152 [M + H] +.

In vitro activity of the compounds of formula (1) 20

The ability of the compounds of formula (1) to act as potent P2 agonists and thereby mediate smooth-muscle relaxation can be determined by the extent of the effect of beta-2 adrenergic receptor stimulation on electric field-stimulated contraction of approx. viatracheal strips.

Caviatrachea Male Dunkin-Hartley guinea pigs (475-525 g) are killed by CO 2 asphyxiation and bleeding from the femoral artery and the trachea is isolated. Four preparations are obtained from each animal, the excision being started immediately below the larynx and 2.5 cm of trachea being taken out. The trachea piece is opened by cutting the cartilage opposite the tracheal muscle, then the transverse sections, 3-4 cartilage leg rings wide, are cut. The resulting strip compositions are suspended in 5 ml organ baths with the help of I cotton threads secured by the upper and lower cartilage bands. The strips are equilibrated, released from stress, for 20 minutes in a modified Krebs Ringer buffer (Sigma K0507) containing 3 μΜ of domethacin (Sigma 17378), 10 μΜ of guanethidine (Sigma I G8520) and 10 μΜ of atenolol (Sigma A7655), heated to I 37eC and gassed with 95% Ο2 / 5% CO2, prior to applying an initial voltage of 1 g. The compositions are allowed to equilibrate for a further 30-45 minutes, during which time they are taken. be re-tensioned (up to 1 g) twice at 15 minute intervals.

Changes in voltage are recorded and monitored via standard isometric transducers coupled to a data collection system (custom designed at Pfizer). Following the equilibrium equilibrium setting, the I tissues are subjected to electrical field stimulation (EFS) using the following parameters: 10 s trains every 2 I 20 minutes, 0.1 ms pulse width, 10 Hz and just-maximum full Continuity (25 volts) continuously for the duration of the experiment. EFS from post-ganglionic cholinergic nerves in the trachea results in smooth muscle monophasic contractions and tensile height is recorded. The organ baths are constantly perfused with the I Krebs Ringer buffer described above using a peristaltic pumping system (pumping rate 7.5 ml / minute) throughout the entire experiment.

I ment, with the exception of as a beta-2 agonist according to I

The present invention is added, the pump becomes

I then stopped for the duration of the cumulative dose

I at the bath and started again after maximum response is I

I reached for the washout period. I

I 1026329- 193

Experimental protocol for determining strength and efficacy

Following equilibrium setting for EFS, the peristaltic pump is stopped and the preparations are "primed" with a single dose of 300 nM isoprenaline (Sigma 15627) to determine a maximum response in terms of inhibition of the contraction-EFS response. The isoprenaline is then washed out for a period of 40 minutes. Following priming and washing out recovery, a standard isoprenaline curve is performed on all tissues (isoprenaline Curve 1) using cumulative, bolus addition to the bath using half-logs in concentration. The concentration range used is 15 to 1/3 * 6 M. At the end of the isoprenaline curve, the compositions are again washed for 40 minutes before starting a second curve, either for isoprenaline (as an internal control) or a Beta-2 agonist of the present invention Beta-2 agonist responses are expressed as percent inhibition of the ESF response Data for Beta-2 agonist are normalized by expressing inhibition as a percentage of the maximum inhibition induced by isoprenaline in curve 1. The EC 50 value for beta-2 agonist of the present invention refers to the concentration of compound required to produce half maximal effect, and data for beta-2 agonists of the present invention are then expressed as relative force to isoprenaline defined by the ratio of 30 (EC50 beta-2 agonist) / (EC50 isoprenaline).

Confirmation of beta-2-mediated functional activity Beta-2 agonist activity of test compounds is confirmed using the above protocol, but prior to constructing the beta-2 agonist curve of the present invention, the pre-2626329- I 194 I pre-incubated (for a minimum of 45 minutes) with 300 nM ICI 118551 (a selective p2 antagonist) I resulting in a beta-2 mediated I effect in a shift to the right of the dose response curve of the test compound.

It has therefore been found that the compounds of formula (1) according to the present invention tested show a relative potency with respect to isoprenaline which is comprised between 0.01 and 10.0.

According to another alternative, the agonist force I for the P2 receptor of the compounds of the formula (1) I can also be determined by the degree of the concentrations of compound according to the present invention required to achieve half a maximum effect (EC50) for produce the P2 receptor.

Preparation of compound I 10 mM / 100% DMSO (dimethyl sulfoxide) stock compound is diluted to obtain top dose in 4% DMSO.

This top dose is used to construct a 10-point half-log dilution curve, all in 4% DMSO. Isoprenalin (Sigma, 1-5627) was used as a standard in each experiment and for control wells on each plate. Given

Vens were expressed as a% isoprenaline reaction. I

I Cell culture I

I CHO (Chinese hamster fallopian tube) that is recombinant I

I the human p2 adrenergic receptor

I (from Kobilka et al., PNAS 84: 46-50, 1987 and Bouvier I

I et al., Mol Pharmacol 33: 133-139, 1988 CH0 hP2)

I grows in Dulbeccos MEM / NÜT MIX F12 (Gibco, 21331-020)

I supplemented with 10% fetal bovine serum (Sigma, F4135, par-I

I 35 tide 90K8404 Exp 09/04), 2 mM glutamine (Sigma, G7513), 500 I

I pg / ml geneticin (Sigma, G7034) and 10 pg / ml puromycin I

I, 1026329-195 (Sigma, P8833). Cells were germinated to give approximately 90% confluence prior to testing.

Assay Method 5 25 μΐ / well of each dose compound was transferred to a cAMP-Flashplate® (NEN, SMP004B), with 1% DM-SO as basal controls and 1Ö0 nM isoprenaline as max controls. This was diluted 1: 2 by the addition of 10 10 μΐ / well PBS. Cells were trypsinized (0.25% Sigma, T4049), washed with PBS (Gibco, 14040-174) and resuspended in stimulation buffer (NEN, SMP004B) to give 1 x 10® cells / ml CHOhP2. Compounds were incubated with 50 ml / well of cells for 1 hour. Cells were then lysed by the addition of 100 μΐ / well detection buffer (NEN, SMP004B) containing 0.18 pCi / ml 125 I-cAMP (NEN, NEX-130) and plates were added for a further 2 hours at room temperature incubated. The amount of 125 I-cAMP bound to the Flashplate® was quantified using a Topcount NXT (Packard), normal counting efficiency for 1 minute. Dose response data were expressed as% isoprenaline activity and adjusted using a four-parameter sigmoid fit.

The compounds according to examples 1 to 27 exhibit a β2 cAMP EC 50 between 0.01 nM and 4 nM.

1026329-

Claims (37)

196 I Conclusions I A compound of the formula: I 5 I. " _tvji "jQ1 · iCO -" ^ v0'1.1 10 Η, Ν N II IOI where the (CH2) n "C (« 0) Q1 group is in the meta or para I position, R1 and R2 are independent are selected from 15 and C 1 -C 4 alkyl, n is 0, 1 or 2 and Q 1 is a group I selected from: I R3, R4, R3, R4, R1, R3, R4, R4, R4, R4, R4 . κι - / Tl T * —N N— \) R * I <cH ^ -y _ / ^ R5 s w \ = / I * ^ N 'r8 L rj r · I 25. . I and a group * -NR-Q 2 -A, where p is 1, 2 or 3, q is 1 or I 2, Q 2 is a direct bond or a C 1 -C 4 alkylene I optionally substituted by OH, RH, C 1 C 1 is alkyl I or phenyl optionally substituted by OH, and A is I C 3 -C 7 cycloalkyl, wherein said cycloalkyl is optionally bridged by one or more carbon atoms, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, pyridyl or a group selected from: R4, R4, R1, R1, R1, R1, R1, R4, R4, R4, R4, R4, R4, R4, R6, R6 and R7 are the same or different and are each independently selected from H, C1 -C4 alkyl, OR9, SR9, halogen, CF 3, OCF 3, (CH 2) 4 COOR 9, SO 2 NR 8 R 9, CONR 8 R 9, NR 8 R 9, NHCOR 8, SO 2 (C 1 -C 4) alkyl and phenyl optionally substituted by hydroxy or hydroxy (C 1 -C 4) alkyl; an integer is selected from 0, 1 and 2, and R8 and R9 are the same or different and are independently selected from H or C1 -C4 alkyl and the * represents the attachment point to the carbonyl group, or, if appropriate, the pharmaceutical acceptable salts and / or isomers, tautomers, solvates or isotope variations thereof. A compound according to claim 1, wherein η is 1 or 2 and Q 1 is -NH-Q 2 -A, wherein Q 2 is a C 1 -C 4 alkylene and. 25. a group R 3 R 4 30 -R 5. 'rt. X is R6, wherein R3, R4, R5, R6 and R7 are as defined in claim 1. 35: A compound according to claim 2, wherein R 3, R 4, R 5, R 6 and R 7 are the same or different and are selected from H), C 1 -C 4 alkyl, OR 9, C 1, F, CF3, Clf F, CF3, OCF3, I COOR9, SO2 NR9 R10, provided that at least I two of R3 to R7 are H, I where R8 and R9 are the same or different and 5 are selected from H or C1 C1-4 alkyl. A compound according to claim 3, wherein R 3, R 4, R 5, R 7 and R 7 are the same or different and are selected from H, CH 3, OH, OCH 3, OCH 2 CH 3, Cl, F, CF 3, OCF 3, COOH, SO 2 NH 2, with the proviso that at least 2 of R 3 to R 7 are H. / 5. A compound according to claim 4, wherein R 1, R 2, R 3, R 4, and R 5 are the same or different and are selected from H , CH 3, OH, OCH 3, OCH 2 CH 3, Cl, F, CF 3, OCF 3, COOH,. I SO 2 NH 2, with the proviso that at least 3 of R 3 to R 7 are H. I 6, A compound according to claim 1, wherein Q 1 'is a group I 20 * -NH-Q 2 -A, wherein Q 2 is a C 1 -C * alkylene and A is H pyridin-2-yl. A compound according to any one of claims 1 to 6, wherein Q 2 is selected from -CH 2 -, - (CH 2) 2 -, - (CH 2) 3 - and I -CH (CH 3) -. A compound according to any one of claims 1 to 6, wherein Q 2 is -CH 2 - '. The compound of claim 1, wherein. η 1 or 2 is I and Q1 is I 1026329 199; R3 is RA 5-7, R6, where R3, R4, R5 and R6 are the same or. are different and are selected from H, C1 -C4 alkyl, OR9, SR9, halogen, CF3, OCF3, COOR9, SO2 NR8R9, CONR®R9, NR8R9, NH-COR8, provided that at least 2 of R3 to R6 are equal are H; "wherein R8 and R9 are the same or different and are selected from H or C1 -C4 alkyl. 10. A compound according to claim 9, wherein R 3, R 4, R 5 and R 6 are the same or different and are selected from H and OR 9, provided that at least 2 of R 3 to R 6 are H; wherein R 9 is selected from H or C 1 -C 4 alkyl. The compound of claim 1, wherein Q1 25 H "CO. . is. 12. A compound according to any one of claims 1 to 11, wherein η is 1. A compound according to any one of claims 1 to 12, wherein R 1 is H and. R2 is CHs. or R1 and R2 are CH3. The compound of claim 1, wherein, n is 0 or 1 and Q 1 is a group of formula: '. 1026329 I 200 I R3 R4 R3 I / \ (e ^ L ^^^ R4 I 5 JI. TR 'IR R6 / Or I · R3 R4 10 / \ HI * ~~ N \ / * \ / - RS I R7 R3 is wherein p is 2 or 3, q is 2 and R3, R4, R5, R6 and R7 are the same or different and are selected from IH and OH, provided that at least one of R3, IR, R5, R 6 and R 7 is OH 20 A compound according to claim 1. wherein n is 0 or 1, R 1 is H or C 1 -C 4 alkyl, R 2 is C 1 -C 4 alkyl, and Q 1 is an I group * -NR-Q 2 -A, wherein A is formula: R 3 R 4 R 4 - I, n, R7, R6, I, I, wherein R, R3, R4, R5, R6, and R7 are as defined in claim 1. I 1026329 The compound of claim 15, wherein R1 is H and R2 is CH3 or R1 and R2 are both CH3. "·. ·" · 201 ". A compound according to any one of claims 15 and 17, wherein R is selected from H, CH 3, CH 2 CH 3 and phenyl substituted by OH. A compound according to any of claims 15 to 17, wherein Q 2 is a direct bond or is selected from -CH 2 * -, - (CH 2) 2 - (^ 2) 4-. -CH 2 -C (CH 3) 2 -, and -CH 2 -CH (OH) -. 19. A compound according to any one of claims 15 to 18, wherein A is a group of formula:, R 3, R 4 / R 5, R 7 V wherein R 3, R 4, R 5, R 6 and R 7 are the same or different and are selected from H, C 1 -C4 alkyl, OR9, Cl, F, CF3, COOR9, SO2 (C1 -C4) alkyl, and phenyl substituted by OH or hydroxy (C1 -C4) alkyl, provided that at least 2 of R3 to R7 are equal to H, and R8 and R® are the same or different and are selected from H or C1 -C4 alkyl. \. " The compound of claim 19, wherein R 3, R 4,. R5, R6 and R7 are the same or different and were selected from H, CH3, C (CH3) 3, OH,. OCH3, OCH2CH3, Cl, F, CF3, CO- OCH 3, SO 2 -CH 2 CH 3, and phenyl substituted by OH or -CH 2 -OH, provided that at least 2 of R 3 to R 7 are equal to H. 1 1026329 (R, R) stereoisomer of a compound according to one of claims 1 to 20. I 202; A compound according to any one of claims 1 to 21, wherein the (CH 2) n -C (= O) Q * group is in the meta position. A compound according to claim 1 selected from the group consisting of: 2- (3 - {(2 R) -2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2- 1-hydroxyethylamino] -propyl} -phenyl) -N-benzyl-acetamide, 1- 2- (3 - {(2 R) -2 - [(2 R) -2- (6-Amino-pyridin-3-yl)) -2-hydroxy-ethylamino] -propyl] -phenyl) -N- (2-methoxy-benzyl) -acetamide, 1- 2- (3 - {(2 R) -2 - [(2 R) -2- (6 -Amino-pyridin-3-yl) -2-hydroxy-ethylamino-propyl-phenyl) -N- (2-ethoxy-benzyl) -acetamide, 2- (3- {(2R) -2) - [(2R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethylamino] -propyl) -phenyl) -N- (3-phenyl-II-propyl) -acetamide, II 2- (3 - {(2 R) -2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethylamino] -propyl) -phenyl) -N-phenethyl-acetamide , II 2- (3 - {(2 R) -2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethylamino] -propyl] -phenyl) -N- (3 , 4-dimethyl-benzyl) -acetamide, II 2- (3 - {(2 R) -2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxyethylamino) ] -propyl) -phenyl) -N-indan-2-yl-1-acetamide, II 2- {3 - {(2R) -2 - [(2R) -2- (6-Amino-pyridin-3-yl) ) -2-II hydroxy-ethylamino] -propyl} -phenyl) -N- (3,4-dichloro-2-benzyl) -acetamide, II 2- (3- {2 - [(2R) -2- (6 -Amino-pyridin-3-yl) -2-hydroxy-II-ethylamino] -propyl} -phenyl) -N- (4-hydroxy-3-methoxy-II-benzyl) -acetamide, II 2 - (4 - {2 -) [(2R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-II-ethylamino] -2-methyl-propyl) -phenyl) -N- {3-methoxy-II-benzyl) -acetamide 1026329 2- (4τ- {2- [(2R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethylamino] -2-methyl-propyl) -phenyl) -N- ( 2, 6-dimethoxy-benzyl) -acetamide, 2- (.3- {2- [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-5-ethylamino] -2-methyl -propyl) -phenyl) -N- (4-sulfamoyl-benzyl) -acetamide, 2- (3- {2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy- ethylamino) -2-methyl-propyl) -phenyl) -N- (2-ethoxy-benzyl) -acetamide, 2- 2- {3- {2 - [(2R) -2- (6-Amino-pyridin-3-) yl) -2-hydroxyethylamino] -2-methyl-propyl) -phenyl) -N-indan-2-yl-acetamide, ... 2- (3- {2 - [(2R) -2- (6 -Amino-pyridin-3-yl) -2-hydroxy-ethylamino] -2-methyl-propyl} -phenyl) -N-benzyl-acetamide, 2- (3- {2 - [( 2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethylamino] -2-methyl-propyl} -phenyl) -N-phenethyl-acetamide, 2- (3- {2 - [( 2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethylamino] -2-methyl-propyl) -phenyl) -N- (3-phenyl-propyl) -acetamide, 2- ( 3- {2 - [(2R) -2- {6-Amino-pyridin-3-yl) -2-hydroxy-ethylamino) -2-methyl-propyl} -phenyl) -N- (3,5-dichloro- benzyi) -acetamide, 2- (3- {2 - [(2R) -2- (6-Amino-pyridin-3-yl) -2-hydroxyethylamino] -2-methyl-propyl) -phenyl) - N- (3,4-dimethyl-benzyl) -acetamide, 2- (3- {2-t (2R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethylamino) -2- methyl-propyl) -phenyl) -N- (3,4-dichloro-benzyl) -acetamide, 2- {3- {2-f (2R) -2- (6-Amino-pyridin-3-yl) - 2-hydroxy-ethylamino) -propyl) -phenyl) -N- (2-fluoro-5-txifluoro-methyl-benzyl) -acetamide; 2- (3- {2- [(2R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethylamino) -propyl) -phenyl) -N- (3-trifluoromethoxy-benzyl) ) -acetamide, 026 3 2 9 I 204 I 2- (3- {2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxyethylamino] -propyl) -phenyl ) - N - (3-fluoro-4-trifluoro-1-methyl-benzyl) -acetamide, 1- 2- (3- {2 - [(2 R) -2- (6-Amino-pyridin-3-yl) -2 -hydroxy-ethylamino] -propyl) -phenyl) -N- (3,4,5-trimethoxy-benzyl) -acetamide, I - (3- {2 - [(2R) -2- (6-amino) pyridin-3-yl) -2-hydroxy-ethylamino] -propyl} -phenyl) -N- (4-trifluoromethoxy-benzyl) -acetamide, 10 2- <3- {2 - [(2R) -2 - (6-Amino-pyridin-3-yl) -2-hydroxy-ethylamino] -propyl} -phenyl) -N- {4-fluoro-2-trifluoro-methyl-benzyl) -acetamide, 2- ( 3- {2 - [(2R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethylamino] -propyl) -phenyl) -N- (5-fluoro-2-trifluoro-I) Methyl-benzyl) -acetamide, 2- (3 - {(2R) -2- [2- (6-Aminopyridin-3-yl) -2-hydroxyethyl-amino) -2-methylpropyl) phenyl] N4- (4'-hydroxybiphenyl-3-ylmethyl) acetamide, II 2- (3 - {(2R) -2- [2- (6-Aminopyridin-3-yl) -2- hydroxyethyl-II amino] -2-methylpropyl) phenyl) -N- (4'-hydroxybiphenyl-4-ylmethyl) acetamide, II 2 - (3 - {(2R) -2 - [(2R) -2- ( 6-Aminopyridin-3-yl) -2-hydroxy-ethylamino] propyl} phenyl} -N- (4'-hydroxybiphenyl-3-yl-methyl) acetamide, II 2- (3 - {(2R)) -2 - [(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-II (ethylamino] propyl} phenyl) -N- (4-hydroxynaphthalen-1-yl-methyl) acetamide, II 3- {2-I (2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl-II-amino] -2-methylpropyl} -N- (4'-hydroxybiphenyl-3-yl-II-methyl) ) benzamide, II - {(2 R) -2- [2- (6-Amino-pyridin-3-yl) -2-hydroxyethyl-II-amino] -2-methyl-propyl) -N- [2- (4 -hydroxy-phenyl) -2-II methyl-propyl] -benzamide, II 3- {2 - [(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl-II-35 amino] -2- methylpropyl) -N- [2- (4-hydroxy-2,5-dimethyl-II-phenyl) -ethyl] -benzamide, II 1026329 3- {2 - ((2R) -2- (6-Aminopyridin-3-yl) - 2-hydroxyethyl-amino] -2-methylpropyl) -N- [2- (4-hydroxy-2,3-dimethyl-phenyl) ethyl] benzamide, 3- {2 - [(2 R) -2- (6-Aminopyridin) -3-yl) -2-hydroxy ethyl 5-amino] -2-methyl-propyl} -N- [2- (4-hydroxy-2-methyl-phenyl-ethyl) -benzamide, 3 - {(2R) -2 - [(2R) -2- (6-Aminopyridin)] 3-yl) -2-hydroxyethylamino] propyl} -N- [2- (4-hydroxy-2,5-dimethyl-phenyl) ethyl] benzamide, 3 - {(2R) -2-i (2R) -2 - (6-Aminopyridin-3-yl) -2-hydroxyethylamino] propyl} -N- [2- (4-hydroxy-2,3-dimethyl-phenyl) ethyl] benzamide, 3 - {(2R) ) -2 - [(2R) -2- (6-Aminopyridin-3-yr) -2-hydroxyethylamino] propyl) -N- [2- (4-hydroxy-2-methylphenyl) -15 ethyl] benzamide, 2- [3- (2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino} -2-methyl-propyl) -phenyl] -N- (3- hydroxy-4-methoxy-phenyl) acetamide, 2 - [3 - (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino} -2-methyl) - propyl) phenyl] - N - (3-hydroxyphenyl) acetamide, v 2- [3- (2 - {[(2R) -2 ~ (6'-Aminopyridin-3-yl) -2-hydroxy-ethyl] ] -amino} -2-methyl-propyl) phenyl] -N- (2-chloro-4-hydroxy-phenyl) acetamide, 2- [3- (2 - {[(2 R) -2 - (. 6-) Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino} -2-methyl-propyl) phenyl] -N- (4-hydroxy-3-methoxy-benzyl) acetamide, 2 - [3 - (2 - { [(2R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethyl] -amino} -2-methyl-propyl) phenyl] -N- [5- (ethyl-30. sulfonyl) -2-hydroxyphenyl] acetamide, 2- [3- (2-U (2R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethyl] -amino} -2-methyl-propyl) phenyl] -N- (2-hydroxy-5-methyl-phenyl) acetamide, 2- [3- {2 - {[(2R) -2- (6-Amihopyridin-3-yl} -2-hydroxy-ethyl] ] -amino} -2-methyl-propyl) phenyl] -N- (5-chloro-2-hydroxybenzyl) acetamide, 1026329 I 206. II 2- [3- (2 - {[<2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino) -2-methyl-propyl) phenyl] -N- (4 -hydroxy-1,1'-biphenyl-3-yl) acetamide, 2- [3- (2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino} -2-methyl-propyl) -phenyl] -N- [2-hydroxy-2- (3-hydroxyphenyl) ethyl] -N-methyl-acetamide, 1- 2- [3- (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2] -hydroxy-ethyl] -amino) -2-methyl-propyl) phenyl] -N-ethyl-N- (3-hydroxyphenyl) acetamide, 10. 2— [3— <2 - {[(2R) -2— (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino} -2-methyl-propyl) phenyl] -N- [2 - (3-ethoxy-4-hydroxy-phenyl) -ethyl] -acetamide, 2- [3- (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] - amino} -2-methyl-propyl) phenyl] -N - {[4 '- (hydroxy-methyl) -1,1'-biphenyl-3-yl] methyl] acetamide, I 2- [3- (2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl) -amino} -2-methyl-propyl) -phenyl] -N- (2,4-dichloro-6- hydroxybenzyl) acetamide, 1 2 - [3 - (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-20'-ethyl] -amino] -2-methyl-propyl) phenyl ] - N - [(3-fluoro-4'-hydroxy-1, 1'-biphenyl-4-yl) methyl] acetamide, 1- 2- [3- (2 - ([(2R) -2- (6 - Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino) -2-methyl-propyl) phenyl] -N - [(4'-hydroxy-1,3-methyl-1,1'-biphenyl) 4-yl) methyl] acetamide, 2- [3- (2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-, ethyl] -amino) -2-] methyl propyl) phenyl] -N- (2-chloro-5-hydroxybenzyl) -N-ethylacetamide, 2- [3- (2 - {[(2R) -2- (6-Aminopyridin-3-)] yl) -2-hydroxyethyl] -ami no) -2-methyl-propyl) phenyl] -N - [(2'-hydroxy-1,1'-biphenyl-2-yl) methyl] acetamide, I 2- [3- (2 - {[(( 2R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethyl] -amino) -2-methyl-propyl) phenyl] -N- [3-hydroxy-5- (trifluoro-methyl) benzyl] -N-methylacetamide, 2- [3- (2- {1 (2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino) -2-methyl-propyl phenyl] -N- (3-chloro-5-hydroxy-benzyl) -N-ethylacetamide, 1026329 207 ''; 2- [3- (2 - {[(2R) -2 -. (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino) -2-methyl-propyl) phenyl] -N- :( 3-chloro-5-hydroxy-benzyl) acetamide, 2- [3- (2- {t (2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-5-ethyl] -amino} -2 -methyl-propyl) phenyl] -N- (4-hydroxy-3,5-dimethylbenzyl) acetamide, 2- [3- (2 - ([(2R) -2- (6-Aminopyridin-3-yl) -2 -hydroxy-ethyl] -amino} -2-methyl-propyl) phenyl] -N-12- (2-hydroxy-phenyl) ethyl) acetamide, 2- [3- (2 - {[(2R) -2-) (6-Aminopyridin-3-yl) -2-hydroxy-ethyl) -amino) -2-methyl-propyl) phenyl] -N-benzyl-N- (4-hydroxyphenyl) acetamide, 2- [3- (2 - {[(2R) -2- (6-amino-pyridin-3-yl) -2-hydroxyethyl) -amino} -2-methyl-propyl) -phenyl] -N- [2- (4-hydroxy-15) phenyl) -ethyl] acetamide, 2- [3- (2- (| (2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino) -2-methyl-propyl) phenyl ] - N - (4-hydroxy-benzyl) acetamide, 2- [3- (2- ([(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino) - 2-methyl-propyl) phenyl] -N- (2-hydroxybenzyl) acetamide,. 2- [3- (2- ([(2R) -2- (6-Aminopyridin-3-yl) -2, -hydroxy-ethyl) -amino) -2-methyl-propyl) -phenyl] -N- (3 hydroxybenzyl acetamide, 25. 2- (3- (2 - ([(2R) -2- (6-Aminopyridin-3-yl)> 2-hydroxyethyl] -amino} -2-methylpropyl) phenyl) -N- [2 - (3-hydroxy-phenyl) -ethyl) -acetamide, 2- [3- (2 - ([(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino) -2 -methyl-propyl) phenyl] -N- [2- (4-hydroxy-3-methoxyphenyl) ethyl] acetamide, Methyl-4 - (([3- (2 - ([(2R) -2- (6- aminopyridin-3-yl) -2-hydroxyethyl] -amino} -2-methyl-propyl) phenyl) acetyl} -amino.) -3-hydroxybenzoate, 2- (3- (2 - ([(2R) -2-) (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino} -2-methyl-propyl) phenyl] -N- (5-tert-butyl-2-hydroxy-phenyl) acetamide, 1026329 I 208 1- 2- [3- (2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino) -2-methyl-propyl) -phenyl] -N- ( 3-hydroxy-4- II methyl-phenyl) acetamide, II 2- [3 - ((2R) -2 ~ {[(2R) -2- (6-Aminopyridin-3-yl) -2- hydroxyethyl] amino) propyl) phenyl] -N- [2M4-hydroxy-II-phenyl) -ethyl] -acetamide, II 2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) ) -2-hydroxyethyl] amino-propyl) phenyl] -N- (4-hydroxybenzyl) -acetamide, II-2- [3 - {(2R) -2 - {[(2R) -2- (β-Am inopyridin-3-yl) -2-hydroxyethyl] amino-propyl) phenyl] -N- (2-hydroxybenzyl) -2-acetamide, II,, 2 - [3 - ((2R) -2 - {[(2R) -2 - (6-Amino-pyridin-3-yl) -2-, 2-hydroxyethyl] amino-propyl) phenyl] -N- (3-hydroxy-benzyl) -1-acetamide, II-2- 3- ((2R) -2- {[ (2RJ-2- (6-Aminopyridin-3-yl) -2-II hydroxyethyl] aminopropyl) phenyl] -N- [2- (3-hydroxy-II phenyl) ethyl] acetamide, II 2- [3 - (( 2R) -2 - {[(2R) -2- (6-phtoinopyridin-3-yl) -2-hydroxyethyl] aminopropyl) phenyl] -N- [2- (4-hydroxy-3-methoxyphenyl) ethyl ] acetamide, II 2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] amino] propyl) phenyl] -N- (5-tert -butyl-2-hydroxyphenyl) acetamide, II 2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2- II> hydroxyethyl] amino) propyl) phenyl] -N- (3-hydroxy-4-methylphenyl) acetamide, II 2- [3 - ((2R) -2 - {[(2R) -2- {6-Aminopyridin-3-yl) - 2- II hydroxyethyl] aminopropyl) phenyl] -N- (3-hydroxy-4- II methoxyphenyl) acetamide, II 2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin) -3-yl) -2- II hydroxyethyl] aminopropyl) phenyl] -N- (4-hydroxy-3-methoxybenzyl) acetamide, II 2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-) yl) -2-hydroxyethyl] amino-propyl) phenyl] -N- [5- (ethyl-sulfonyl) -2-hydroxyphenyl] acetamide, II 1026329 209 '. ·; 2- [3 .-- ((2R) -2- {[(2R) -2- (6-Aminopyridin-3-yl) -2- hydiroxyethyl] amino} propyl) phenyl] -N- (2 -hydroxy-5-methylphenyl) acetamide, 2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-5 hydroxyethyl] amino) propyl) phenyl ] -N- {3-hydroxy-2-methylphenyl) acetamide, 2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] amino] propyl ) phenyl] -N- (5-chloro-2-hydroxybenzyl) -acetamide, 2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2 - hydroxyethyl] amino} propyl) phenyl] -N- [2-hydroxy-2- (3-hydroxy-phenyl) ethyl] -N-methyl-acetamide, f 2 - [3 - ((2R) -2 - {[ (2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] aminopropyl) phenyl] -N- [2- (3-ethoxy-4-15 hydroxyphenyl) ethyl] acetamide.de, 2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] amino-propyl) -phenyl] -N- [2- (3-hydroxy-4-methoxy-phenyl) ) ethyl] acetamide, 2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-20 hydroxyethyl] amino) propyl) phenyl] -N- ethyl N- [2- (4-hydroxyphenyl) ethyl] acetamide., 2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] ] aminopropyl) phenyl] -N - (2-chloro-4-hydroxybenzyl) -N-ethyl acetamide, 2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-) yl) -2-4 hydroxyethyl] amino} propyl) phenyl] -N- (5-hydroxy-1,2,3,4-tetrahydronaphthaleri-1-yl) acetamide, 2- [3- ((2R) -2-) {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] amino-propyl) -phenyl] -N- (4-hydroxyphenyl) -30-acetamide, 2 - [3 - ((2R) -2) {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] amino] propyl) phenyl] -N- [4- (4-hydroxyphenyl) butyl] acetamide, 2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-35 hydroxyethyl] aminopropyl) phenyl] -N ^ [(4'-hydroxy-1'-biphenyl-4-ylmethyl] acetamide] 1026329 210; 2- (3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino-propyl) -phenyl] -Ν - {[4 '- (hydroxy - methyl) -1,1'-biphenyl-3-yl) methyl} acetamide, 1 2-13 - ((2R) -2 - {((2R) -2- (6-Aminopyridin-3-yl) -2) - hydroxyethyl] aminopropyl) phenyl] -N- (2,4-dichloro-6-hydroxybenzyl) acetamide, 2- (3 - ((2R) -2 - {[(2R) -2- ( 6-Aminopyridin-3-yl) -2-hydroxyethyl) -amino-propyl) -phenyl) -N - ((3-fluoro-4'-hydroxy-1,1'-biphenyl-4-yl) methyl] acetamide, I 2- (3 - ((2R) -2- {f (2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] amino} propyl) phenyl] -N - [(4'- hydroxy-3-methyl-1 * 1'-biphenyl-4-yl) methyl] acetamide, 1- 2- [3 - ((2R) -2 - {((2R) -2- (6-Aminopyridin-3-) yl) -2-hydroxyethyl] amino-propyl) phenyl] -N- (2-chloro-5-hydroxybenzyl) -N-ethylacetamide, 1- 2- [3 - ((2R) -2 - {[(2R) - 2- (6-Aminopyridin-3-yl) -2-hydroxyethyl-amino-propyl) -phenyl] -N - [(2'-hydroxy-1,1'-biphenyl-2-yl) methyl] acetamide, I 2- [3- ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] aminopropyl) phenyl) -N- [3-hydroxy-5- (trifluoro-methyl) benzyl] -N-methylacetamide, 2- [3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] amino] propyl) phenyl] -N- (3-chloro-5-hydroxybenzyl) -N-ethylacetamide, 2- (3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2- I / hydroxyethyl] aminopropyl) phenyl] -N- (3-chloro-5-hydroxybenzyl) acetamide, 2- (3- ((2R) -2 - ([(2R) -2- (6-Aminopyridin-3-) yl) -2-hydroxyethyl] aminopropyl] phenyl] -N- (4-hydroxy-3,5-dimethylbenzyl) acetamide, 2- (3- ((2R) -2 - {[(2R) -2 - (6-Aminopyridin-3-yl) -2-hydroxyethyl] aminopropyl) phenyl] -N- (3,5-dichloro-2-hydroxybenzyl) acetamide, 3- (2 - {[(2R) - 2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1,3 amino} -2-methyl-propyl) -N- [2- (4-hydroxyphenyl) ethyl] benzamide, 1026329 211. 3 - (2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino) -2-methyl-propyl) -N- (4-hydroxybenzyl) benzamide, 3- (2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino) -2-methyl-propyl) -N- (2-hydroxybenzyl) benzamide, 5- 3- (2- { [(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] - f. amino) -2-methyl-propyl) -N- [2- (3-hydroxyphenyl) ethyl] -benzamide, 3- (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2- hydroxyethyl] -amino) -2-methyl-propyl) -N- [2- (4-hydroxy-3-methoxy-phenyl) -ethyl] benzamide, 3- (2 - {[(2R) -2- (6-) Aminopyridin-3-yl) -2-hydroxyethyl] -amino) -2-methyl-propyl) -N- (3-hydroxy-4-methylphenyl) -benzamide, 3- {2 - {[(2R) -2- ( 6-Aminopyridin-3-yl) -2-hydroxyethyl] -15 amino} -2-methyl-propyl) -N- [2- (4-hydroxy-3,5-dimethoxyphenyl) ethyl] benzamide, 3- ( 2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino) -2-methyl-propyl) -N- (3-hydroxy-4-methoxyphenyl) -benzamide, 20 3- (2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino} -2-methyl-propyl) -N- (3-hydroxyphenyl) benzamide, 3- ( 2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino} -2-methyl-propyl) -N- (4-hydroxy-3-methoxy-benzyl) -benzamide 3- (2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino} -2-methyl-propyl) -N-f5- (ethylsulfonyl) -2- hydroxyphenyl] benzamide, 3- (2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino} -2-methyl-propyl) - N- (3-hydroxy-2-methylphenyl) -30 benzamide, 3- (2-U (2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -amino) -2-methyl-propyl ) -N- (5-chloro-2-hydroxybenzyl) -benzamide, 3- (2 - {[(2R) -2- (6-Amihopyridin-3-yl) -2-hydroxyethyl] -35 amino} -2- methyl propyl) - N - (4-hydroxy-1,1'-biphenyl-3-yl) benzamide, 1026329 I 212 I 3- (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) ) -2-hydroxyethyl] -1-amino} -2-methyl-propyl) -N- [2-hydroxy-2- (3-hydroxy-phenyl) -ethyl) -N-methyl-benzamide, 1- 3- (2- {1 ( 2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -5 amino} -2-methyl-propyl) -N- (2-hydroxybenzyl) -N-methyl-benzamide, 1- 3- ( 2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] amino) -2-methyl-propyl) -N- (3,5-dichloro-2-hydroxy-benzyl) benzamide, 3- (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1-amino) -2-methyl-propyl) -N- [2- ( 2-hydroxyphenyl) ethyl] benzamide, 3- (2 - ([(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1 amino} -2-methyl- propyl) -N- [2- (3-ethpxy-4-hydroxy-phenyl) ethyl] benzamide, 3- (2 - {[(2 R) -2- (6-Aminopyridi) n-3-yl) -2-hydroxyethyl] -1-amino] -2-methyl-propyl) -N- [2- (3-hydroxy-4-methoxy-phenyl) -ethyl] -benzamide, II 2- [3- (2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino) -2-methyl-propyl) -benzoyl] -1, 3,4,5-I tetrahydro-1 H -2-benzazepin-8-ol, 1- (2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl) -1 amino) -2-methyl-propyl ) - N - [(4'-hydroxy-3-methyl-1,1'-biphenyl-4-yl) methyl] benzamide,. . 3- (2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl] -1 (amino) -2-methyl-propyl) .- N- [(3'- hydroxy-1,1'-biphenyl-1-2-yl) -methyl) -benzamide, II 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2- hydroxy-ethyl) -amino-propyl) -N- (5-chloro-2-hydroxybenzyl) -l 2 benzamide, II 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-) yl) -2-hydroxy-II-ethyl] -amino-propyl) -N- [2-hydroxy-2- (3-hydroxyphenyl) -1-ethyl) -N-methyl-benzamide, II 3 - ((2R) -2 - {[(( 2 R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethyl-amino-propyl) -N- (2-hydroxy-benzyl) -N-methyl-benzamide, 1026329'131 "3- ((2RJ.-2- {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino-propyl) -N- [2- {3-ethoxy-4-hydroxyphenyl] -ethyl ] -benzamide, 3- ((2R) -2 - {. [(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-5-ethyl) -amino] -propyl] -N- [2- (3- hydroxy-4-methoxyphenyl) ethyl] benzamide, 2- [3 - {(2 R) -2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2- hydroxyethyl] -amino] propyl) benzoyl ) -2.3, 4,5-tetrahydro-1H-2-benzazepin-8-ol, 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-y 1) -2-hydroxyethyl] -amino} propyl) -N-ethyl-N- [2- (4-hydroxyphenyl) -ethyl) benzamide, 3- ((2R) -2-Π (2R) -2 - (6-Amino-pyridin-3-yl) -2-hydroxy-ethyl) -4-amino} -propyl) -N- (2-chloro-4-hydroxy-benzyl) -N-15-ethylbenzamide, 3- ((2R) -2 - {[(2R) -2- (6-Amino-pyridin-3-yl) -1-2-hydroxy-ethyl] -amino-propyl) -N- (5-hydroxy-1,2,3,4-tetrahydro-naphthalen-1) -yl) benzamide, 2- {4- [3 - ((2R) -2 - {[(2R) -2- {6-Aminopyridin-3-yl) -2-; Hydroxyethyl] -amino-propyl) -benzoyl] -piperazin-1-yl) -phenol, 3- ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -aminojpropyl) -N- (4-hydroxyphenyl) benzamide, 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-25.ethyl] -aminojpropyl ) - N - [4- (4-hydroxyphenyl) butyl] -, benzamide, 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxyethyl) ] -amino) propyl) -N- [H'-hydroxy-1'-biphenyl-4-ylbenzamide, 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) ) -2-Hydroxy-ethyl] -amino-propyl) -N - {[4 '- (hydroxymethyl) -1,1'-biphenyl-3-yl) methyl) benzamide; 3 - ({2 R) -2 - {[(2 R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino-propyl) -N- (2,4-dichloro-6-hydroxy- Benzyl) benzamide, 1026329 214 I - - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino-propyl) -N - [(3-fluoro-4) '-hydroxy-1,1' - biphenyl-4-yl) methyl] benzamide, 1-3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2- hydroxy-ethyl-amino-propyl) -N - [(4'-hydroxy-3-methyl-1,1-biphenyl-4-yl) methyl] benzamide,. 1-3 - ((2R) -2- {£ (2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino) -propyl) -N- (2-chloro-5-) hydroxybenzyl) -N-ethylbenzamide, 1 - 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino} -propyl) ) - N - [(2'-hydroxy-1,1'-biphenyl-2-yl) methyl] benzamide, 1- 3- ((2R) -2 - {[(2R) -2- (6-Aminopyridin) 3-yl) -2-hydroxy-ethyl] -amino} -propyl) -N - [(4'-hydroxy-1,1'-biphenyl-2-yl) methyl] benzamide, 1-3 - ({2 R) - 2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino-propyl) -N- [3-hydroxy-5- (trifluoromethyl) -1-benzyl] -N- methylbenzamide, 1-3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino-propyl) -N- (3-chloro-5) -hydroxy-benzyl) -N-1-ethylbenzamide, 1-3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino-propyl) - N- (3-chloro-5-hydroxybenzyl) -1 benzamide, 1,3 - ((2R) -2 - {[(2R) -2 - '(6-Aminopyridin-3-yl) -2-hydroxy-1-yl) ethyl] -amino) propyl) -N - {(4'-hydroxy-1,1'-biphenyl-3-yl) methyl) benzamide,. 1-3 - ((2R) -2-U (2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino-propyl) -N- (4-hydroxy-3,5-dimethyl) - benzyl, benzamide, 1-3 - ((2R) -2 - {[(2R) -2- (6-aminopyridin-3-yl) -2-hydroxy-ethyl] -amino} -propyl) -N- (3,5-dichloro-2-hydroxy-benzyl) benzamide, 1-3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-35) ethyl] -amino) propyl) -N- [2- (2-hydroxyphenyl) -ethyl) -1 benzamide, I 1026329 1-3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin)] 3-yl) -2-hydroxy-ethyl] -amino} -propyl) -N- (3-hydroxy-4-methoxyphenyl) -: benzainide, 3 - ((2R) -2 - {[(2R) -2- ( 6-Aminopyridin-3-yl) -2-hydroxy-5-ethyl] -amino} -propyl) -N- (3-hydroxyphenyl) ben2amide, 3 - ((2R) -2 - ([(2R) -2- (6 -Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino} propyl) -N- (4-hydroxy-3-methoxybenzyl) -benzamide, 3 - ((2R) -2 - {[(2R) -2 - (6-Amino-pyridin-3-yl) -2-hydroxy-ethyl-amino-propyl) -N- [5- (ethylsulfonyl) -2-hydroxy-phenyl] benzamide; 3 - ((2R) -2 - {((2R) -2- (6-Amino-pyridin-3-yl] -2-hydroxy-ethyl] -amino) -propyl) -N- (2-hydroxy-5-methylphenyl) benzamide, 3 - ((2R) -2 - ([(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino} -propyl) -N- (3-hydroxy -2-methylphenyl) benzainide, 3 - ((2R) -2 - {[{2R) -2- (6-Amino-pyridin-3-yl) -2-hydroxy-ethyl] -amino} -propyl) -N- [2 - (4-hydroxyphenyl) ethylbenz-20 amide, 3 - ((2R) -2 - {((2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino) propyl) - N- (4-hydroxybenzyl) benzamide, 3 - ((2R) -2 - {[(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino} -propyl) -N- (2-hydroxybenzyl) benzamide, 3- ((2R) -2- {[(2R) -2- (6-Aminopyridin-3-yl) -1'-2-hydroxyethyl] -amino} propyl) - N- (3-hydroxybenzyl) benzamide, and .3- ((2R) -2- ([(2R) -2- (6-Aminopyridin-3-yl) -2-hydroxy-ethyl] -amino) -propyl] -N - [2- (3-hydroxyphenyl) ethyl] benzamide. A process for the preparation of a compound of formula (1) as described in any one of claims 1 to 23 or a pharmaceutically acceptable salt or derivative. form thereof, characterized in that it comprises the following step of (a) coupling an acid of formula (3): 1026329 I 216 I OH OI IV-WY A 0 H (3) 15 XJ rA * Uhch> ( ) Prot-NT n K1 where Prot is a protecting group, and R1, R2 are II and n as defined in claim 1, II with an amine of formula NRH-Q2-A (4.1), II R3 R <R3 I ( CHS) «KrA55; Y / R4 II ,, (c ^ · \ J ^ rs I hnA \ || ^ RS IIR» (4.2), R »(4.3), II R3 R * II 20 hi / ^ \ —RS II 'or R' R · (4.4) II wherein p, q, R 3, R 4, R 5, R 6 and R 7 are as defined in claim 1, and II 1, (b) removing the protective group "Prot" II of the compound of formula (2), II OH OII, XYVtCHV0 '(2) IA, <iA_. R1 P2 II Prot-NN .. II 1026329 to form the 2-amino-pyridine derivative of formula (1 ) I 2 I 35, I 3 I (3) isolating said compound of formula I 4 I (i) I A pharmaceutical composition comprising a. compound of the formula (1) as described in any one of claims 1 to 23 or. a pharmaceutically acceptable salt or derived form thereof, together with conventional pharmaceutically harmless excipients and / or additives. . . A compound of the formula (1) as described in any one of claims 1 to 23 or a pharmaceutically acceptable salt, derived form or preparation thereof, for use as a medicament. . A compound of the formula (1) as described in any one of claims 1 to 23 or a pharmaceutically acceptable salt, derived Form Or preparation thereof, for use in the treatment of diseases, conditions and ailments wherein the P 2 receptor is concerned. 20 A compound with the formula (1). as described in any one of claims 1 to 23 or a pharmaceutically acceptable salt, derived form or preparation thereof, for use in the treatment of diseases, conditions and ailments selected from the group consisting of: . Asthma of any type, aetiology, or pathogenesis, in particular asthma that is a member selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, atopic. bronchial IgE-mediated asthma ,. bronchial. asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiological disturbances, extrinsic asthma caused by environmental factors, essential asthma with unknown or unclear cause, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise induced 1026 3 2 9 I 218 · I asthma, allergen-induced asthma, cold II air-induced asthma, occupational asthma, infectious II asthma caused by bacterial, fungal, protozoa, or viral infection, non-allergic asthma II 5 ma , starting asthma, panting child syndrome and source II chiolytis, chronic or acute trachea narrowing ,. chronic II bronchitis, small airway obstruction, and II emphysema, II 10 'obstructive or inflammatory airway diseases of any type, etiology or pathogenesis, in particular an obstructive or inflammatory airway disease that is a member selected from the group II consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), II COPD which includes chronic bronchitis, emphysema or dyspnea associated or unconnected with II COPD, COPD characterized by irreversible, II progressive airway obstruction, adult respiratory distress syndrome (ARDS), exacerbation of airway II hyperreactivity due to other drug therapy and airway disease associated with lung high blood pressure, II 'bronchitis of any type, etiology or pathogenesis, in particular bronchitis which is an II member selected from the group consisting of a cute II bronchitis, acute laryngotracheal bronchitis, II arachidic bronchitis, catarrhal bronchitis, II croupus bronchitis, dry bronchitis, infectious II asthmatic bronchitis, productive bronchitis, II staphylococcus or streptococcal bronchitis and II vesicle bronchitis, I · acute bronchitis any type, etiology II or pathogenesis, in particular bronchiectase which II is a member selected from the group consisting of cylindrical bronchiectase, bladder-shaped bronchi II, fusion-shaped bronchiectase, capillary bronchiectase, cystic bronchiectase, dry bronchiectase and follicular bronchiectase. Use of a compound of the formula (1) as described in any one of claims 1 to 23 or of a pharmaceutically acceptable salt, derived form or composition thereof, for the preparation of a medicament with a P2 agonist activity. 10 30. Use of a compound of the formula (1) as described in any one of claims 1 to 23 or of a pharmaceutically acceptable salt, solvate or composition thereof, for the preparation of a medicament for the treatment of diseases, conditions and ailments selected from the group as described in claim 28. 31. Combination of a compound according to any of claims 1 to 23 with other therapeutic agents selected from: (a) 5-lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists, (b ) Leukotriene antagonists (LTRAs) including antagonists of LTB4, LTC4, LTD4, and LTE4; (c) Histamine receptor antagonists including H1 and H3 antagonists; Fit, (e) Muscarinic M3 receptor antagonists or anti-cholinergic agents, (f) PDE inhibitors, eg PDE3, PDE4 and PDE5 inhibitors, (g) Theophylline, (h) Sodium cromoglycate, (i) COX inhibitors both non-selective and selective COX-1 or COX-2 inhibitors (NSAIDs), 1026329 I 220 I (j) Oral and inhaled glucocorticosteroids, (k) Monoclonal antibodies active against endogenous inflammatory units, (1) Anti-tumor necrosis factor (anti-TNF-α) agents, I 5 (m) Adhesion molecule inhibitors including VLA-4 antagonists, (n) Kinine B1 and B2 receptor antagonists, I (o) Immune suppressants, (p) Inhibitors of matrix metalloproteases (MMPs), II (q) Tachykinin NK1, NK2 and NK3 receptor antagonists, I (r) Elastase inhibitors, I (s) Adenosine A 2a receptor agonists, I (t) Inhibitors of urokinase, I (u) Compounds acting on dopamine receptors, I eg D2 agonists, I (v) Modulators of the NFicP path, e.g. IKK inhibitors, (w) Agents that can be classified as I mucolytics or anti-cough medicine, and I (x) Antibiotics. I I 1026329